Implantable thermal treatment method and apparatus

ABSTRACT

A long-term implantable ultrasound therapy system and method is provided that provides directional, focused ultrasound to localized regions of tissue within body joints, such as spinal joints. An ultrasound emitter or transducer is delivered to a location within the body associated with the joint and heats the target region of tissue associated with the joint from the location. Such locations for ultrasound transducer placement may include for example in or around the intervertebral discs, or the bony structures such as vertebral bodies or posterior vertebral elements such as facet joints. Various modes of operation provide for selective, controlled heating at different temperature ranges to provide different intended results in the target tissue, which ranges are significantly effected by pre-stressed tissues such as in-vivo intervertebral discs. In particular, treatments above 70 degrees C., and in particular 75 degrees C., are used for structural remodeling, whereas lower temperatures achieves other responses without appreciable remodeling.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. provisionalapplication serial Nos.: 60/351,875 filed Jan. 23, 2002; and 60/351,827filed on Jan. 23, 2002; and 60/410,603 filed on Sep. 12, 2002; and also60/411,401 filed on Sep. 16, 2002. The disclosures of these U.S.provisional patent applications are herein incorporated in theirentirety by reference thereto.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not Applicable

REFERENCE TO A COMPUTER PROGRAM APPENDIX

[0003] Not Applicable

BACKGROUND OF THE INVENTION

[0004] 1. Field of the Invention

[0005] The present invention is an implantable surgical device systemand method for delivering therapeutic levels of energy to tissue in aliving body. More specifically, it is a long-term implantable system andmethod for delivering therapeutic levels of ultrasound energy invasivelywithin the body in order to treat chronic disorders associated withskeletal joints. Still more specifically, it is a long-term implantsystem and method for delivering therapeutic ultrasound energy to spinaljoints, such as in particular intervertebral discs or associated bonyvertebral structures.

[0006] 2. Description of the Background Art

[0007] For many years, much research and commercial development has beendirected toward delivering energy to tissue in order to achieve variousdesired therapeutic results. Examples of energy modalities previouslydescribed for tissue treatment include: electrical current (both DC andAC, e.g. radiofrequency or “RF” current), plasma ion energy, sonicenergy (in particular ultrasound), light energy (e.g. laser, infrared or“IR”, or ultraviolet or “UV”), microwave induction, and thermal energy(e.g. convection or conduction). Other modalities for treating tissueinclude without limitation: cryotherapy (cooling tissue to desiredlevels to affect structure of function), and chemical therapy(delivering chemicals to the tissue to affect the tissue structure offunction). Each of these energy delivery and other treatment modalitieshas been extensively studied and characterized as providing uniquebenefits, as well as unique issues and concerns, with respect to tissuetherapy. Accordingly, many specific energy delivery methods and systemshave been disclosed to provide unique benefits for particular intendedtherapeutic applications.

[0008] Various specific tissue responses to energy delivery have alsobeen observed and reported during the course of significant study andcharacterization. In one regard, tissues or their function may bedamaged by energy delivery such as thermal therapy. Examples ofpreviously disclosed, differentiated effects of thermal tissue therapygenerally characterized to damage tissue include, without limitation:ablation (which has been defined as either molecular dissociation or byachieving cellular necrosis), coagulation, degranulation, anddesiccation. Alternatively, energy delivery in certain particular formshas also been characterized as promoting reproductive stimulation incertain tissues. Certain desired results have been disclosed withrespect to intending controlled tissue damage with tissue thermaltherapy; other desired results have been disclosed with respect topromoting tissue reproduction with tissue thermal therapy. In any event,because of the pronounced effects observed from tissue energy delivery,it is often desired to control and accurately select the localization oftissue/energy interaction in order to treat only the intended tissue,else normal surrounding tissue is effected with harmful results.

[0009] Accordingly, the different energy delivery modalities have beenspecifically characterized as providing particular benefits and problemsversus other modalities with respect to various specific tissues andrelated medical conditions. Examples of specific medical conditions andrelated tissue that have been studied and characterized for tissueenergy delivery include: tumors such as cancer (e.g. liver, prostate,etc.); vascular aneurysms, malformations, occlusions, and shunts;cardiac arrhythmias; eye disorders; epidermal scarring; wrinkling; andmusculo-skeletal injury repair. The nature of the condition to betreated, as well as the anatomy of the area, can have significant impacton the desired result of energy delivery, which directly differentiatesbetween the appropriateness or inappropriateness of each of thedifferent energy delivery modalities for such application (as well asthe corresponding particular operating parameters, systems, and methodsfor delivering such energy).

[0010] Depending upon the particular energy modality, various differentparameters may be altered to affect the thermal effect in particulartissues, including which type of effect is achieved (e.g. ablation,coagulation, desiccation, etc.), as well as depth or degree of theeffect in surrounding tissues. For the purpose of a generalunderstanding, however, known tissue responses to thermal therapies,e.g. effect of changing temperatures to particular levels, have beenpreviously characterized for certain tissues in prior disclosures whichare summarized as follows.

[0011] As described above, temperature elevation of biological tissuesis currently used for outright tissue destruction or to modify tissuesto enhance other therapies. Low temperature elevations (41-45° C.) ofrelatively short duration (<30-60 min) have been disclosed as beingassociated with cell damage, but generally only to such extent to berepairable and considered non-lethal. In this range, it is believed thatheat mediated physiological effects include heat induced acceleration ofmetabolism or cellular activity, thermal inactivation of enzymes,rupture of cell membranes, and delayed onset of increasing blood flowand vessel permeability. Prior disclosures addressing temperatureexposures in excess of 45° C. and/or longer durations have stated thatcellular repair mechanisms no longer function due to denaturation of keyproteins or can't keep up with the accumulating damage. According tothermal therapy at such temperatures, complete cell death and necrosishave been observed in certain particular tissues to be fully expressedin approximately 3-5 days. Temperature exposures in the 42-45° C.regimen are commonly used for example as an adjuvant to radiation cancertherapy and chemotherapy, and have been considered for enhancing genetherapy and immunotherapy as well. Higher temperature elevations (50+°C.) have been investigated for inducing desirable physical changes intissue, ranging from applications such as controlled thermal coagulationfor “tightening” ligaments and joint capsules, tissue reshaping, andselective tissue thermal coagulation for destroying cancerous and benigntumors. High temperature exposures (50+° C.) are generally believed toproduce rather lethal and immediate irreversible denaturation andconformational changes in cellular and structural proteins in varioustissues, thereby thermally coagulating such tissues.

[0012] In general, heat-induced cell damage or tissue structural changesdescribed above are believed to be attributed to thermal denaturationand aggregation of key protein structures. The accumulation of thisthermal damage can be modeled using the Arrhenius rate process equation,which establishes a relationship between rate of thermal damage and theduration and temperature of exposure: $\begin{matrix}{{\frac{1}{\tau} = {A \cdot ^{{- \Delta}\quad {E/{RT}}}}},} & (1)\end{matrix}$

[0013] where ΔE is activation energy (J mol⁻¹), R is the universal gasconstant (8.32 J mol⁻¹ K⁻¹), A is the rate constant (s⁻¹), T istemperature in Kelvin, and 1/τ is rate of thermal damage (s⁻¹). Usingthis expression (Eqn. 1), a relationship can be derived to determine anexposure time(τ₂) and/or temperature elevation (T₂) required to producean equivalent observed biological effect associated with a specifiedtemperature (T₁) and time exposure (τ₁). This is the basis of thethermal iso-effect equation as shown below, which is non-linear withrespect to temperature exposure and linear with respect to exposuretime:

τ₂=τ₁ e ^((ΔE/RT) ^(₁) ^(T) ^(₂) ^()(T) ^(₁) ^(−T) ^(₂) ⁾=τ₁ K ^((T)^(₁) ^(−T) ^(₂) ⁾,   (2)

[0014] where the parameter K is approximated as constant for typicaltherapeutic temperature elevations (10-30° C.). Furthermore, extensivein vitro and in vivo studies have demonstrated that ΔE for thermaldamage is approximately constant at 140 J mol⁻¹ for temperatures greaterthan 43° C. Thus, the relationship between time and temperature for agiven biological effect depends upon activation energy only. Thus, asdetermined from the hyperthermia biology literature, K≅2 for T≧43° C.and K≅4-6 for T<43° C. The different values split at approximately 43°C. in order to model the biphasic behavior in the rate response, withfaster damage accumulation after a break around 43° C. These values holdfor lethal cellular damage, but not coagulation of structural proteins(collagen). Traditionally this iso-effect dose has been used tocharacterize hyperthermia cancer treatments with a target temperatureelevation of 42.5-45° C., and has led to 43° C. becoming the historicalreference dose temperature. This forms the basis of the thermaliso-effect dose (TID) equation, which as shown below can be used tocalculate thermal dose of a varying temperature exposure over time as anequivalent exposure duration at 43° C. (or other reference temperature).Temperature time history is equated to a thermal dose at a knowntemperature reference. $\begin{matrix}{{{EM}_{43} = {{\int_{0}^{t_{f}}{K^{({T - 43})}{t}}} = {\sum\limits_{t = 0}^{t_{final}}{\Delta \quad {tK}^{({T - 43})}}}}},} & (3)\end{matrix}$

[0015] where dt is a time step (min) and EM₄₃ is thermal dose expressedin equivalent minutes at 43° C.

[0016] Various previously published disclosures have verified theArrhenius model and the iso-effect relationship of differenttemperature-time exposures for generating trans-epidermal thermalnecrosis in skin. Applying the TID analysis, a threshold ofapproximately 320 EM₄₃ (wherein “EM” represents “equivalent minutes” atthe given temperature shown in subscript) as found for temperaturesbetween 44-60° C. Thermal dosages between 10-100 EM₄₃ have been shown tocorrelate with improved response to hyperthermia and radiation therapy.For a conservative approach 250 EM_(43° C.) is a threshold dose forcomplete thermal necrosis, where reported values range from 25-240 EM43°C. for brain and muscle tissue, respectively.

[0017] In addition, thermal coagulation or coagulation necrosis havebeen disclosed to occur in tissues exposed to temperatures greater thanapproximately 55° C. for a duration of minutes, in particular respect tocollagen in certain structures studied. Thermal coagulation of softtissues generally takes place only for temperatures in excess of 50° C.Numerous investigators have validated the “TID” (or “temperatureiso-dose”) concept for predicting lesions using 240-340 EM 43° C. as athreshold dose and critical temperatures of 53-54° C. for coagulatingmuscle.

Therapeutic Energy Delivery for Spinal Disorders

[0018] Spinal disorders have been the topic of significant study andcommercial development for therapeutic energy delivery. In particular,various specific conditions that have been studied with respect toparticular modes of therapeutic energy delivery.

[0019] Of particular interest has been chronic lower back pain. Chroniclow back pain is a significant health and economic problem in the UnitedStates, being the most costly form of disability in the industrialsetting. For a substantial number of these patients the intervertebraldisc is considered the principal pain generator. Traditionally, patientswho fail conservative therapy have few treatment options besidediscectomy or fusion, either of which can result in significantmorbidity and variable outcomes. Recent efforts have been directedtoward investigating thermal therapy for providing a healing effect oncollagenous tissues, and therefore this modality has been incorporatedinto several minimally invasive back pain treatments.

[0020] Early orthopedic use of high temperature heat therapy was tomanage shoulder instability. In this application, the shoulder capsuleis treated with laser or radio-frequency (RF) thermal energy totemperatures typically in the range of 70 to 80° C. This treatment hasbeen disclosed to stabilize the joint by inducing tissue contraction.Such treatment also has been disclosed to result in an acute decrease instiffness (e.g. as much as 50%) that may be recovered due to biologicremodeling. However, the long-term benefits of this treatment have beenquestioned since the collagenous tissue may re-lengthen over time.

[0021] The contraction associated with thermal therapy, which can reachas high as 50% along the fiber direction in the shoulder capsule, hasbeen correlated with thermal denaturation. Thermal denaturation is anendothermic process in which the collagen triple helix unwinds after acritical activation energy is reached. Differential scanning calorimetry(DSC) is a technique to measure both the denaturation temperature(T_(m)—the peak temperature corresponding to this critical activationenergy) and the total enthalpy of denaturation (ΔH—the total energyrequired to fully denature the collagen). This technique can be used tocorrelate thermal exposure with the resulting degree of denaturation fora specific collagenous tissue, and thus to guide the development of anoptimal thermal dose.

[0022] Intradiscal electrothermal therapy (IDET) has been recentlyintroduced as a minimally invasive, non-operative therapy in which atemperature elevation is applied in order to treat discogenic low backpain. In this procedure, a temporary catheter containing a 5 cm longresistive-wire heating coil is introduced percutaneously into the discunder fluoroscopic guidance. The internal temperature of the device isthen raised from 65° C. to 90° C. over a course of 16 minutes. Thisprocedure is intended to produce temperatures sufficient to contractannular collagen and ablate annular nociceptors. A controlled, 12 monthtrial of IDET on a relatively small patient population (36 individuals)demonstrated some relief of back pain in 60% of patients and totalrelief in 23%. A two-year follow-up study of 58 patients was disclosedto result in clinically significant improvement in pain, physicalfunction, and quality of life. While these results have been consideredby some to be promising, prospective placebo-controlled trials arelacking, and the therapeutic mechanisms of thermal therapy are unknown.Proposed therapeutic mechanisms of such technique have included: 1)collagen denaturation, causing annular stiffening, and tissueremodeling; 2) annular de-innervation; and 3) ablation ofcytokine-producing cells. Due to mechanistic uncertainty, treatmentoptimization and patient selection are generally empirically based.

[0023] The effect of heat on collagen denaturation and biomechanicalproperties has been investigated in various tissues: knee and shouldercapsule, tendon, and chordae tendineae. In general, at least one priordisclosure reports that significant denaturation and shrinkage occurredin tissue treated at 65° C. and above for 1-5 minutes. However, giventhat the annular architecture of intervertebral discs is quite differentfrom these other tissues it is has not been previously made clear thatprior results can be directly extrapolated to the intervertebral disc.

[0024] Further more detailed background information related to variousaspects of thermal tissue therapy and/or chronic back pain is variouslydisclosed in the following publications: Amonoo-Kuofi, H. S., 1991,“Morphometric changes in the heights and anteroposterior diameters ofthe lumbar intervertebral discs with age.” J Anat 159-68; Arnoczky, S.P. and Aksan, A., 2001, “Thermal modification of connective tissues:basic science considerations and clinical implications.” Instr CourseLect 3-11; Chen, S. S., Wright, N. T. and Humphrey, J. D., 1997,“Heat-induced changes in the mechanics of a collagenous tissue:isothermal free shrinkage.” J Biomech Eng 4, 372-8; Chen, S. S., Wright,N. T. and Humphrey, J. D., 1998, “Heat-induced changes in the mechanicsof a collagenous tissue: isothermal, isotonic shrinkage.” J Biomech Eng3, 382-8; Dewey, W. C., 1994, “Arrhenius relationships from the moleculeand cell to the clinic.” Int J Hyperthermia 4, 457-83; Flandin, F.,Buffevant, C. and Herbage, D., 1984, “A differential scanningcalorimetry analysis of the age-related changes in the thermal stabilityof rat skin collagen.” Biochim Biophys Acta 2, 205-11; Gerber, A. andWarner, J. J., 2002, “Thermal capsulorrhaphy to treat shoulderinstability.” Clin Orthop 400, 105-16; Hall, B. K., 1986, “The role ofmovement and tissue interactions in the development and growth of boneand secondary cartilage in the clavicle of the embryonic chick.” JEmbryol Exp Morphol 133-52; Hayashi, K. and Markel, M. D., 2001,“Thermal capsulorrhaphy treatment of shoulder instability: basicscience.” Clin Orthop 390, 59-72; Hayashi, K., et al., 2000, “Themechanism of joint capsule thermal modification in an in-vitro sheepmodel.” Clin Orthop 370, 236-49; Hayashi, K., et al., 1997, “The effectof thermal heating on the length and histologic properties of theglenohumeral joint capsule.” Am J Sports Med 1, 107-12; Heary, R. F.,2001, “Intradiscal electrothermal annuloplasty: the IDET procedure.” JSpinal Disord 4, 353-60; Hecht, P., et al., 1999, “Monopolarradiofrequency energy effects on joint capsular tissue: potentialtreatment for joint instability. An in vivo mechanical, morphological,and biochemical study using an ovine model.” Am J Sports Med 6, 761-71;Karasek, M. and Bogduk, N., 2000, “Twelve-month follow-up of acontrolled trial of intradiscal thermal anuloplasty for back pain due tointernal disc disruption.” Spine 20, 2601-7; Kronick, P., et al. 1988,“The locations of collagens with different thermal stabilities infibrils of bovine reticular dermis.” Connect Tissue Res 2, 123-34; LeLous, M., et al. 1982. “Influence of collagen denaturation on thechemorheological properties of skin, assessed by differential scanningcalorimetry and hydrothermal isometric tension measurement.” BiochimBiophys Acta 2, 295-300; Lopez, M. J., et al., 2000, “Effects ofmonopolar radiofrequency energy on ovine joint capsular mechanicalproperties.” Clin Orthop 374, 286-97; Miles, C. A. and Ghelashvili, M.1999, “Polymer-in-a-box mechanism for the thermal stabilization ofcollagen molecules in fibers.” Biophys J 6, 3243-52; Naseef, G. S., etal., 1997, “The thermal properties of bovine joint capsule. The basicscience of laser- and radiofrequency-induced capsular shrinkage.” Am JSports Med 5, 670-4; Nieminen, M. T., et al., 2000, “Quantitative MRmicroscopy of enzymatically degraded articular cartilage.” Magn ResonMed 5, 676-81; (Nrc/Im), N. R. C. A. I. O. M. (2001). “MusculoskeletalDisorders and the workplace: low back and upper extremities.” WashingtonD.C., National Academy Press; Saal, J. A. and Saal, J. S., 2002,“Intradiscal electrothermal treatment for chronic discogenic low backpain: prospective outcome study with a minimum 2-year follow-up.” Spine9, 966-73; discussion 973-4; Saal, J. S. and Saal, J. A., 2000,“Management of chronic discogenic low back pain with a thermalintradiscal catheter. A preliminary report.” Spine 3, 382-8; Schachar,R. A., 1991, “Radial thermokeratoplasty. Int Ophthalmol” Clin 1, 47-57;Schaefer, S. L., et al., 1997, “Tissue shrinkage with theholmium:yttrium aluminum garnet laser. A postoperative assessment oftissue length, stiffness, and structure.” Am J Sports Med 6, 841-8;Schwarzer, A. C., et al., 1995, “The prevalence and clinical features ofinternal disc disruption in patients with chronic low back pain.” Spine17, 1878-83; Urban, J. P. and Mcmullin, J. F., 1985, “Swelling pressureof the intervertebral disc: influence of proteoglycan and collagencontents.” Biorheology 2, 145-57; Vangsness, C. T., Jr., et al., 1997,“Collagen shortening. An experimental approach with heat.” Clin Orthop337, 267-71; Vujaskovic, Z., et al., 1994, “Effects of intraoperativehyperthermia on peripheral nerves: neurological and electrophysiologicalstudies.” Int J Hyperthermia 1, 41-9; Wallace, A. L., et al., 2000, “Thescientific basis of thermal capsular shrinkage.” J Shoulder Elbow Surg4, 354-60; and Wallace, A. L., et al., 2002, “Creep behavior of a rabbitmodel of ligament laxity after electrothermal shrinkage in vivo. Am JSports Med 1, 98-102. The disclosures of these references are hereinincorporated in their entirety by reference thereto.

[0025] Chronic lower back pain (e.g. discogenic lumbar pain) and relatedmotor nerve deficit is typically due to damaged or herniated vertebraldiscs which either directly impinge on surrounding nerves or causeirritating inflammation. Traditional treatment options include surgery,anti-inflammatory drugs, physical therapy, etc., with surgery typicallythe last option. Due to difficulty of surgical procedure, complicationsand time of recovery, alternative procedures have been investigated.Recently, intradiscal thermal therapy has been introduced as aminimally-invasive alternative in the treatment of various spinaldisorders such as chronic low back pain and otherwise disorders relatedto intervertebral disc abnormalities.

[0026] In particular, several different systems and methods have beendisclosed for treating various abnormal conditions associated withintervertebral discs specifically by delivering electrical current inthe RF range during invasive treatment procedures in and around the discwithin the body. Other previously disclosed examples intended toinvasively deliver therapeutic levels of energy in order to treatvarious spinal disorders include delivery of plasma ion energy (e.g.CoblationR from Arthrocare, Inc.), laser light energy, or thermal energyfrom conductive heating elements (e.g. the SpineCATH IDEC procedure,commercially available from Oratec Interventions, introduced above). Atleast one other prior disclosure is intended to deliver heatedthermoplastic material to allow it to flow into and then set uponcooling within the nucleus of an intervertebral disc in order to replacethe nucleus pulposus.

[0027] Further more detailed examples of energy delivery systems andmethods such as of the types just described, that are intended toprovide invasive therapy to treat various conditions associated withintervertebral disc disorders are variously disclosed in the followingissued U.S. Pat. Nos. 4,959,063 to Kojima; 6,264,650 to Hovda et al.;6,264,659 to Ross et al. Examples are also disclosed in the followingpublished U.S. patent application: US 2001/0029370 to Hodva et al. Otherexamples are disclosed in the following published international patentapplications: WO 00/49978 to Guagliano et al.; WO 00/71043 to Hovda etal.; WO 01/26570 to Alleyne et al.;. Additional disclosure is providedin the following published reference: Diederich C J, Nau W H,Kleinstueck F, Lotz J, Bradford D (2001) “IDTT Therapy in CadavericLumbar Spine: Temperature and thermal dose distributions, ThermalTreatment of Tissue: Energy Delivery and Assessment,” Thomas P. Ryan,Editor, Proceedings of SPIE Vol. 4247:104-108. The disclosures of allthese references provided in this paragraph are herein incorporated intheir entirety by reference thereto.

[0028] Ultrasound energy delivery and the effects of such energy onvarious different tissue structures has been the topic of significantrecent study. The particular benefits of ultrasound delivery have beensubstantially well characterized, in particular with respect todifferent types of tissues as well as different ultrasound energydeposition modes. Many different medical device systems and methods havebeen disclosed for delivering therapeutic levels of ultrasound totissues to treat wide varieties of disorders, including for examplearterial blockages, cardiac arrhythmias, and cancerous tumors. Suchdisclosures generally intend to “ablate” targeted tissues in order toachieve a desired result associated with such particular conditions,wherein the desired response in the particular tissues, and theultrasound delivery systems and methods of operation necessary for thecorresponding energy deposition modalities, may vary substantiallybetween specific such “ultrasound ablation” systems and methods.

[0029] Further more detailed examples of ultrasound delivery systems andmethods such as of the type just described are disclosed in thefollowing issued U.S. Pat. Nos. which are incorporated herein byreference: 5,295,484 to Marcus et al.; 5,620,479 to Diederich; 5,630,837to Crowley; 5,733,280 to Sherman et al.; 6,012,457 to Lesh; 6,024,740 toLesh et al.; 6,117,101 to Diederich et al.; 6,164,283 to Lesh; 6,245,064to Lesh et al.; 6,254,599 to Lesh et al.; and 6,305,378 to Lesh et al.Other examples are disclosed in the following published foreign patentapplications which are incorporated herein by reference: WO 00/56237 toMaguire et al.; WO 00/67648 to Maguire et al.; WO 00/67656 to Maguire etal.; WO 99/44519 to Langberg et al.

[0030] In addition, ultrasound enhanced drug delivery into tissues, e.g.to increase dispersion, permeability, or cellular uptake of therapeuticcompounds such as drugs, has been well characterized and disclosed inmany different specific forms.

[0031] Further more detailed examples of ultrasound energy deliverysystems and methods such as those just described are disclosed in thefollowing U.S. Pat. Nos. References: 5,725,494 to Brisken; 5,728,062 toBrisken; 5,735,811 to Brisken; 5,846,218 to Brisken et al.; 5,931,805 toBrisken; 5,997,497 to Nita et al.; 6,210,393 to Brisken; 6,221,038 toBrisken; 6,228,046 to Brisken; 6,287,272 to Brisken et al.; and6,296,619 to Brisken et al. The disclosures of these references areherein incorporated in their entirety by reference thereto.

[0032] Additional previously disclosed examples for ultrasound energydelivery systems and methods are intended to treat disorders associatedwith the spine in general, and in some regards of the intervertebraldisc in particular. However, these disclosed systems are generallyadapted to treat such disorders chronically from outside of the body,such as for example via transducers coupled to a brace worn externallyby a patient. Therefore locally densified US energy is not achievedselectively within the tissues associated with such disorders invasivelywithin the body. At least one further disclosure, however, proposesdelivering focused ultrasound energy from outside the body for theintended purpose of treating intervertebral disc disorders, inparticular with respect to degenerating the nucleus pulposus to reducethe pressure within the disc and thus onto the adjacent spinal cord.However, the ability to actually achieve such targeted energy deliveryat highly localized tissue regions associated with such discs, and toaccurately control tissue temperature to achieve desired results,without substantially affecting surrounding tissues has not been yetconfirmed or taught.

[0033] Further more detailed examples of such systems and methodsintended to treat spinal disorders with ultrasound energy from outsideof the body are variously disclosed in the following issued U.S. Pat.Nos. 5,762,616 to Talish; 6,254,553 to Lidgren et al. Other examples aredisclosed in the following published international patent applications:WO 97/33649 to Talish; WO 99/19025 to Urgovich et al.; and WO 99/48621to Cornejo et al. The disclosures of these references are hereinincorporated in their entirety by reference thereto.

[0034] Exposure of soft and hard tissue, including the spine and joints,to varied degrees of heat or other energy delivery can provide variedtherapeutic effects. For example, heat at high temperatures and thermaldoses can shrink tissues, change the structural matrix, and generatephysiological changes and/or kill cells. Heat at low temperatures andcan generate permeability changes or changes in the cellulartransport/metabolism that increase effectiveness or deposition ofcertain pharmaceutical agents.

[0035] Heat can be provided using ultrasound (US), radio frequency (RF),laser, and the like, using invasive or non-invasive applicationtechniques. For example, in order to treat internally embeddedsensitized nerves or cells making inflammatory factors, invasivetechniques are preferred so that the heat source can be placed in closeproximity to the target tissue. This can be accomplished usingconventional surgical techniques, where the patient is opened, and aheat source is inserted directly (e.g., using a directly implantabledevice such as described in U.S. Pat. No. 5,620,497, incorporated hereinby reference), or indirectly through a catheter or other deliverydevice. When the procedure is complete, the heat source is removed andthe patient is closed.

[0036] However, despite the many benefits of temporary devices and theiracutely delivered treatments, a single treatment or a contemporaneousseries of discrete treatments in those previous examples may not provideadequate results in many cases. In one regard, the ability to treat manychronic ailments is limited in the setting of an acute invasion into thebody required by temporary devices. Therefore, it may be necessary torepeat the treatment at a later date if a single application is notsufficient for the ailment. Accordingly, longer term implantable devicesand treatments are preferred for many medical therapies.

[0037] In this regard, the term “temporary” as herein used to describecertain medical devices, systems, or methods, including with respect toimplants, is intended to mean adapted for acute use, such as in ahospital or outpatient surgical room or suite, over a relatively shortperiod of time. In general, patients do not carry temporary devicesimplanted within them away from a healthcare facility—they are used inan acute setting typically accompanied by observation by healthcarepersonnel (e.g. such observation by a healthcare provided may be eithercontinuous, or for longer temporary treatments may be sporadic, or maysimply initiate a procedure via an implant and return to remove it aftera time specified or an endpoint parameter is met). The time period bywhich temporary medical devices are typically left indwelling within thebody is usually on the order of minutes, or possibly hours, though insome extreme cases some temporary medical devices can be left indwellingfor as much as 1-5 days (though again typically under professional care,such as during a hospital stay). Temporary medical devices also ofteninclude portions of the device extending externally of the patient'sbody, such as for example catheters or leads that interface with othercooperating hardware such as actuators or diagnostic systems.

[0038] In contrast, the terms “permanent implant” are herein intended tomean a medical device implant that is intended for long-termimplantation for chronic therapy or use. In such cases, patient's carrysuch implant indwelling within their bodies during their daily lives.Typically, these permanent implants are intended for indefinite periodsand associated with chronic conditions ameliorated or diminished by thepermanent implant, but typically not cured upon removal of the permanentimplant. As such, they are not generally intended to be removed, thoughoften may require removal, such as for replacement due to limitation ofthe lifespan of the implant itself, or for example changing condition ofthe patient. Such changing conditions may include, for example andwithout limitation: growth with respect to pediatric patients, otherchanges in physique, changes in condition being treated or otherwisewith respect to the environment and/or needs underlying the implant'spresence.)

[0039] The terms “semi-permanent implant” are herein intended to meanimplants that are intended for implantation over a period that lastslonger than considered under an “acute” setting, e.g. longer thantypically provided for under the care of a healthcare provider andlonger than most “temporary” medical devices such as temporary implants,though usually over a shorter period than most “permanent implants”.Semi-permanent implants are typically carried indwelling within thepatient away from the healthcare facility and out from under the directobservation of a professional caregiver. They most usually remainindwelling during the patient's daily living for a period of days,possibly weeks, and possibly in some cases even years. These implantsare generally intended to be carried within the patient for a limitedperiod of time, however, and then to be removed.

[0040] Moreover, the terms “long-term” where herein used to describe animplantable device, or related system or procedure, include bothpermanent and semi-permanent implants unless otherwise specificallyindicated or would be otherwise readily apparent to one of ordinaryskill. Moreover, the use of the terms “permanent implant” generallycontemplate similar application with respect to “semi-permanentimplants” unless otherwise specifically indicated or readily apparent tobe exclusive to one of ordinary skill.

[0041] Various medical device systems and methods have been disclosedrelated to chronic treatment of various medical disorders by deliveringenergy to tissue from permanent or semi-permanent implants. Many suchprior disclosures relate specifically to providing implantableelectrical energy delivery devices, and in particular relation to spinalcord stimulation. Many of such devices are intended to be long-termimplants.

[0042] One example of a disclosed method of using a spinal cordstimulation lead involves implanting the lead in the epidural space andincludes an elongate lead paddle located at the distal end of the lead.An array of electrodes is located on the lead paddle. The array has atleast three columns of electrodes and includes a column having at leastone electrode positioned substantially over the midline of the leadpaddle, a column of at least one electrode positioned laterally of themidline on one side thereof, and a column of at least one electrodepositioned laterally of the midline on the other side thereof. At leastone of the columns within the array has more than one electrode. Each ofthe electrodes is interconnected by a conductor to a respective terminalat the proximal end of the lead. The lead is implanted such that themidline of the lead paddle is positioned over the midline of the spinalcord. Each electrode is independently selectable such that the spinalcord may be stimulated unilaterally or bilaterally.

[0043] Another example of an apparatus for multi-channel transverseepidural spinal cord stimulation uses a multi-channel pulse generatordriving a plurality of electrodes mounted near the distal end of a lead.These electrodes are mounted in one or more lines, generallyperpendicular to a lead axis, and having a planar surface along onesurface of the lead. The lead is implanted adjacent to the spinal corddura mater with the electrodes transverse and facing the spinal cord.Pulses generated by the pulse generator for each channel are normallysimultaneous, of equal amplitude and of equal duration, however thepulse generator is arranged such that pulses for each channel canselectably alternate in time, can selectably be of unequal amplitude, orboth. The changes in pulse timing and magnitude permit shifting theelectrical stimulation field and the resulting paresthesia pattern afterinstallation to accommodate improper lead placement or postoperativedislocation and to minimize unwanted motor responses.

[0044] A wide variety of spinal stimulation energy delivery systems andmethods have been disclosed, generally with respect to providingelectrical current to cause a nervous stimulation to produces a changein some innervated bodily function. For example, at least one disclosureinvolves an apparatus providing timed electrical stimulus pulses in thefluid of the sacral canal to conduct electrical stimulus to the spinalcord to stimulate miturition and certain muscles in paraplegic mammals,e.g. to evacuate the bladder. In another example, a method forelectrical spinal cord stimulation was disclosed for treating orgasmicdysfunction. Stimulating electrodes are placed in the spinal canal via aneedle inserted between the appropriate vertebrae in parallel with thespinal cord. The electrodes are connected to a power source. Throughvariable transmission of electrical signals a patient suffering fromorgasmic dysfunction may once again achieve orgasm.

[0045] Long-term, electrical spinal cord stimulation has been widelyinvestigated for treating various types of pain, such as back pain inparticular, as well as other types of pain such as angina.

[0046] According to at least one example, a facet joint pain reliefmethod and apparatus is disclosed that depolarizes the medial branch ofthe spinal nerve associated with a painful facet joint so as to blockpain impulses from reaching the spinal cord. The preferred apparatusincludes a neurostimulator and two or more electrodes which carryelectrical pulses to the target nerve or nerves. The impulses areintense enough to cause depolarization of a given medial branch and itsarticular branches, but not so large as to cause depolarization of thespinal cord itself. The stimulator in one regard is physically small andbattery operated, facilitating implantation underneath the skin. Thestimulator includes a controller and appropriate electronics operativeto generate electrical impulses tailored to an individual's need forappropriate pain relief in terms of pulse frequency, pulse width, andpulse amplitude. In an alternative embodiment, the stimulator furtherincludes electrodes and electrical circuitry operative to monitormyoelectrical activity generated by the surrounding muscles and modulatethe impulses generated by the stimulator to meet the demands of theindividual's activity and/or prolong battery life.

[0047] Another example provides a method and apparatus for providingfeedback to spinal cord stimulation for angina treatment. Techniques forcardiac monitoring and angina pectoris treatment using a cardiaccondition detector and stimulating electrode are disclosed. The detectorand electrode are implanted, and angina is relieved by transmittingelectrical pulses to the stimulating electrode while the patient isgiving an indication of an ischemic event that otherwise would beindicated by the angina.

[0048] A variety of mechanisms have been previously disclosed that areintended to provide paths to and into bony structures of the spine fordelivering a spinal implant there. Many disclosures have intended toaddress maintaining position of electrodes during electrical coupling totissue. Several disclosures provide techniques intended for implanting alead with therapy delivery elements, such as electrodes or drug deliveryports, within vertebral or cranial bone so as to maintain those elementsin a fixed position relative to a desired treatment site. Additionaltechniques have been intended for non-invasively positioning andre-positioning the therapy delivery elements after implantation intosuch bone cavities. Further technique is disclosed using a positioncontrol mechanism and/or a position controller for adjusting in situ theposition of the therapy delivery elements relative to the targetedtissue. The therapy delivery elements may be positioned laterally in anydirection relative to the target, or toward or away from the treatmentsite. These techniques have been particularly intended for use withelectrical stimulation or drug infusion to the targeted tissue.

[0049] Another disclosure provides an apparatus for providing a therapyin or through one or more trans-sacral axial instrumentation/fusion(TASIF) bore through vertebral bodies in general alignment withvisualized, anterior or posterior axial instrumentation/fusion line(AAIFL or PAIFL) in a minimally invasive, low trauma manner andproviding a therapy to the spine employing the trans-sacral axial bore.Anterior or posterior starting positions aligned with the AAIFL or PAIFLare accessed through respective anterior and posterior tracts. Curved orrelatively straight anterior and curved posterior TASIF bores are formedfrom the anterior and posterior starting positions. The therapiesperformed through the TASIF bores include ductoscopy, full and partialdiscectomy, vertebroplasty, balloon-assisted vertebroplasty, drugdelivery, electrical stimulation and various forms of spinal disc cavityaugmentation, spinal disc replacement, fusion of spinal motion segments,and radioactive seeds implantation. Axial spinal implants and bonegrowth materials can also be placed in the TASIF bores.

[0050] Various disclosures have also been intended to provide feedbackcontrol for either adjusting the positioning of therapy deliveryelements or other aspects of therapy, and in particular relation tospine therapy delivery elements.

[0051] In one group of examples, an apparatus and technique forelectrical stimulation of the central or peripheral nervous system basedupon changes in the position of a patient is disclosed. A positionsensor is chronically implanted in the patient, such as in one specificexample a mercury switch position sensor which indicates whether apatient is erect or supine. This position information is used by achronically implanted pulse generator to vary the stimulation intensity.The intensity may be controlled by changes in pulse amplitude, pulsewidth, number of pulses per second, burst frequency, number of pulsesper burst, electrode polarity, or other convenient parameter whichaccomplishes the particular medical purpose within an application. Theoutput of the chronically implanted pulse generator is applied to thespinal cord, peripheral nerves, and/or targets in the brain with leadsand electrodes in a manner consistent with the given medical need. Suchstimulation is useful in the treatment of chronic intractable pain,hemodynamic insufficiency resulting in angina, peripheral vasculardisease, cerebral vascular disease, various movement disorders, andbowel and bladder control.

[0052] Another example is directed toward living tissue stimulation andrecording techniques with local control of active sites. Implantableelectrodes are adapted to interact with electrically excitable tissueare selected by an implantable, programmable controller that receivespower form a main cable and data from a data conductor that identifiesthe stimulation and recording electrodes to be activated. Theimplantable controller enables electrical signals to be transmittedbetween a distal site of power generation and a selected subset ofmultiple electrodes with a minimum number o conductor wires.

[0053] Long-term electrical stimulus, such as via long-term implants,has also been investigated for promoting bone growth, in particularrelation to the spine, as follows.

[0054] According to one general example, two electrodes are implantedinto the tissue near the base site for bone growth. The electrodes arecoupled to a bone growth stimulator which generates an alternatingcurrent that stimulates bone growth. Other examples using electricalstimulus to promote bone growth abound, in particular with respect tobony structures and implants related to the spine.

[0055] In one additional example, an implantable growth tissuestimulator and method is disclosed with a hand-held programmer/monitorfor programming and monitoring an implantable tissue growth stimulator.The stimulator includes circuitry for implementing selected operationsin response to a down-link signal transmitted by the programmer/monitor,various circuits such as control circuit and transmit/receive circuit isused for transmitting up-link and down-link signals to and from theimplantable bone growth stimulator.

[0056] According to another example a preformed extendable mesh cathodefor an implantable bone growth stimulator has been disclosed. Anelectrical signal generator is provided connected with an anode and aprefabricated wire mesh cathode that is extendable to at least twice itspreformed initial length. The cathode in a preferred embodiment includesa single chain of conductive wire links formed as alternating loops andtwists of two strands of monofilament titanium wire.

[0057] Still another example apparatus has been disclosed for thedelivery of electric current for interbody spinal arthrodesis.Electrical current is delivered to an implant surgically implantedwithin the intervertebral space between two adjacent vertebrae of thespine to promote bone growth and the fusion process to areas adjacent tothe implant. The implant is self-contained with a surgicallyimplantable, renewable power supply and related control circuitry fordelivering electrical current directly to the implant and thus directlyto the area in which the promotion of bone growth is desired. Thedesired areas of bone growth promotion are intended to be controlled byconducting negative charge only to the desired location of promotion.

[0058] A further disclosed example provides direct current stimulationof spinal interbody fixation device has also been disclosed. A spinalfusion stimulator has an interbody fustion cage or other interbodyfixation device adapted to be implanted in the intervertebral disc spaceof a patient's spine, the interbody fusion cage having a hollow bodywith internal and external conductive surfaces. The stimulator includesa constant current generator connected to the interbody fusion cage andset to provide a DC current effective to produce a surface currentdensity of at least 1 uA/cm² in the interbody fusion cage whenimplanted.

[0059] Additional long-term electrical delivery implant devices andrelated methods have been disclosed for other intended uses related forexample to neural stimulation, nerve regeneration, and musclestimulation.

[0060] At least one published example provides for nerve regeneration byway of electrical stimulus as follows. In vivo mammalian nerveregeneration of a damaged nerve is attempted by using an electriccurrent through the damaged nerve while the nerve ends are abuttedagainst one another, sutured together or spaced apart from each other.The apparatus is intended to be implantable in a human body so that theelectric current can be maintained for an extended period of time toproduce regeneration of the damaged nerve.

[0061] Various disclosures have also intended to provide percutaneousintramuscular stimulation electrodes, such as for treating shoulderdysfunction in patients who have suffered disruption of the centralnervous system such as a stroke, traumatic brain injury, spinal cordinjury, or cerebral palsey. An external microprocessor basedmulti-channel stimulation pulse train generator is used for generatingselect electrical stimulation pulse train signals. In another example, aclosed-loop, implanted-sensor (e.g. force sensor), functional electricalstimulation system for partial restoration of motor functions isprovided.

[0062] Further more detailed examples of devices, systems, and methodssimilar to those described above, such as with respect to long-termenergy delivery implants, spinal therapy implants, or related devicesand methods providing additionally helpful understanding, are variouslydisclosed in one or more of the following issued U.S. Pat. Nos.4,569,351 to Tang; 4,750,499 to Hoffer; 4,774,967 to Zanakis et al.;5,031,618 to Mullett; 5,282,468 to Klepinski; 5,342,409 to Mullett;5,417,719 to Hull et al.; 5,441,527 to Erickson et al.; 5,501,703 toHolsheimer et al.; 5,565,005 to Erickson et al.; 5,643,330 to Holsheimeret al.; 5,766,231 to Erickson et al.; 5,824,021 to Rise; 6,014,588 toFitz; 6,038,480 to Hrdlicka et al.; 6,112,122 to Schwardt et al.;6,120,502 to Michelson; 6,169,924 to Meloy et al.; 6,171,239 toHumphrey; 6,270,498 to Michelson; 6,292,699 to Simon et al.; 6,319,241to King et al.; and 6,436,098 to Michelson. Additional devices, systems,and methods are disclosed in the following U.S. patent applicationPublications: US 2001/0053885 to Gielen et al.; 2002/0111661;2003/0014088 to Fang et al. Additional examples are also disclosed inthe following PCT patent application Publications: WO 99/56818 to Racz;and WO 00/78389 to Fitz. Another device is shown in the following U.S.Design Patent: Des. 361,555 to Erickson et al. The disclosures of thesereferences listed variously throughout this paragraph are hereinincorporated in their entirety by reference thereto.

[0063] Notwithstanding substantial benefits gained by many of thelong-term implantable devices and chronic therapy methods previouslydescribed, each generally has respective limitations and shortcomingsconcomitant with their specified indications for use and with respect tocertain therapies to which they are not generally applicable.

[0064] For example, the various disclosed not generally adapted toprovide thermal therapy the many electrical therapy devices describedare specially adapted to provide electrical nervous stimulus, and. Evento the extent thermal therapy may or would be delivered, however, suchelectrical devices and methods have shortcomings in their ability todeliver adequate thermal therapy to tissue as required, in particular inand around the spine, and in particular in a manner that penetratesstructures sufficient to provide relatively deep heating from the energydelivery element, and/or that is controlled, directed, or focused forhighly localized thermal treatment. Moreover, the various previouslydisclosed references do not adequately accommodate the need to controland isolate temperatures if thermal therapy were to be delivered, whichis highly advantageous in particular during thermal treatment ofstructures in and around the spinal cord.

[0065] Still further, none of the previous disclosures noted aboveprovide adequate devices and/or methods for controlling long-termthermal therapy of various tissues associated with skeletal joints,again in particular the spine, in order to achieve isolated, desiredresults such as thermal remodeling of tissue support structures (inparticular stressed structures such as collagenous tissues ofintervertebral discs), controlled cellular necrosis (including either incombination with or exclusive of tissue remodeling), or cellularregeneration or stimulation, or enhanced drug delivery.

[0066] At least two ultrasound systems and methods have been disclosedthat are intended to provide ultrasound energy delivery to tissue vialong-term implantable devices in order to treat chronic medicalconditions such as of the types generally introduced above with primaryrespect to electrical energy delivery.

[0067] For example, ultrasonic techniques have been disclosed for usingultrasonic imaging to assist in neurostimulator control wherein theprimary therapeutic energy delivery is electrical. A lead adapted to beimplanted adjacent to a spinal cord located within a spinal column of avertebrate in order to facilitate stimulation of the spinal cord oradjacent tissue. An ultrasonic transmitter/receiver produces anultrasonic sound wave that creates ultrasonic echo waves reflected froma predetermined portion of the spinal cord and generates a distancesignal related to the distance between the transducer/receiver and thepredetermined portion of the spinal cord. The distance signal is used toadjust the amplitude of an electrical stimulation signal that stimulatesthe spinal cord or adjacent tissue so that the value of the stimulationsignal tends to remain uniform in spite of changes in the relativedistance between the transducer/receiver and the predetermined portionof the spinal cord. Accordingly, such use of ultrasound is as adiagnostic tool, and generally not therapeutic US energy delivery.

[0068] In another example, an apparatus and method that stimulates withultrasound the growth of a tissue or produces an image at a site withina patient is disclosed. A housing may be subcutaneously implanted withinthe patient such that the ultrasound is directed toward the site. Agenerator disposed within the housing produces a signal, which atransducer converts into ultrasound. The transducer is partiallydisposed within the housing. The device may include an imaging circuitfor processing ultrasound echoes received by the transducer to generateimages of the tissue at the site. A remote control may be used tocontrol the device while it is implanted within the patient.

[0069] Further more detailed examples of ultrasound devices and methodsrelated to neurostimulator control and/or stimulating tissue growth aredisclosed in the following issued U.S. Pat. Nos. 5,524,624 to Tepper etal.; and 5,628,317 to Starkebaum et al. The disclosures of thesereferences are herein incorporated in their entirety by referencethereto.

[0070] Despite the benefits that such implantable ultrasound devicesprovide, they are still limited as to the ability to provide a widevariety of important long-term ultrasound therapies via permanent orsemi-permanent implantable transducers. Moreover, other desirablefeatures that are not provided by various of the prior electricalstimulation systems and methods are also not provided by theseultrasound devices and methods.

[0071] There is still a need for a long-term thermal or ultrasoundtherapy implant system that is adapted to provide one or more of thefollowing beneficial features affecting the desired therapy: active andlocalized cooling of targeted and/or non-targeted tissues, use ofultrasonically transmissive coupling members to enhance energy deliveryat the tissue interface, directionality, focusing and/or collimation ofthe US energy delivery, substantial depth of heating, and temperatureand dosing controls around values adapted to provide various intendedtissue responses (in particular within stressed tissues such as inspinal joints).

[0072] Moreover, the devices and related noted above lack the ability toprovide additional benefits that may be harnessed from controlled,long-term ultrasound energy delivery into certain tissues in order toachieve a variety of desired tissue responses.

[0073] There is still a need for an improved, long-term implantablethermal therapy system that can be activated when necessary overprolonged periods of time in order to provide long term therapy topatients' joints, such as in particular spinal joints, in addition toother tissues in the body.

[0074] There is in particular still a need for a long-term, implantableultrasound therapy system adapted to provide long-term ultrasounddelivery to treat chronic ailments not adequately treated or cured byacute thermal therapy treatments.

[0075] There is also still a need for providing long-term thermaltherapy to tissue, and in particular stressed tissue such as found inspinal joints, that allows for sufficient thermal doses to be deliveredto achieve certain intended results according to lower elevatedtemperatures and over longer periods of time than otherwise currentlyavailable.

[0076] There is also still a need for a long-term implantable thermaltherapy system and method that is adapted to provide long term,directional energy delivery into tissue within the body, in particulartissue associated with joints, and further more particularly spinaljoints.

[0077] There is still a need for a system and method for locallydelivering therapeutic amounts of ultrasound energy from long termimplants within the body in order to treat disorders associated with thespine and other joints or tissues.

[0078] There is also still a need for a system and method adapted tolocally deliver ultrasound energy to a highly localized region oftissue, such as only a portion of a disc associated with a spinal joint,when needed over long periods of time and without requiring multiple,repeat surgeries.

BRIEF SUMMARY OF THE INVENTION

[0079] An object of the invention is to deliver long-term, therapeuticlevels of ultrasound energy to intervertebral discs in order to treatdisorders associated therewith.

[0080] Another object of the invention is to provide a kit of long-term,implantable energy delivery devices with varied shapes along the energydelivery portion thereof in order to specifically treat differentregions of intervertebral discs having varied geometries from within thenucleus.

[0081] Another object of the invention is to deliver therapeutic levelsof energy over long-term duration and sufficient to cause necrosis ofparticular cellular structures associated with an intervertebral discwithout substantially remodeling or affecting the structure integrity ofthe annulus fibrosus of the disc.

[0082] Another object of the invention is to provide long-term, thermaltherapy to a region of tissue associated with a joint in the bodywithout substantially remodeling structural support tissues associatedwith the joint.

[0083] Another object of the invention is to treat chronic inflammationand pain associated with disorders of the spine in general andintervertebral discs in particular.

[0084] Another object of the invention is to denervate or necrosenociceptive fibers or cells in certain regions of tissue associated withan intervertebral disc.

[0085] Another object of the invention is to reduce chronic inflammationassociated with damaged intervertebral discs.

[0086] Another object of the invention is to provide long-termimplantable devices for repairing damaged regions of intervertebraldiscs.

[0087] Another object of the invention is to achieve cellular necrosisof certain particular tissues associated with an intervertebral discdisorder without substantially altering the structure of the annulusfibrosus of the respective disc.

[0088] Another object of the invention is to remodel cartilaginoustissue associated with spinal joints, and in particular intervertebraldiscs.

[0089] Another object of the invention is to provide sufficient thermaltherapy to a region of stressed tissue to cause a remodeling of thetissue over prolonged treatment periods.

[0090] Another object of the invention is to provide sufficient thermaltherapy to a region of an intact mammalian intervertebral disc to causea remodeling of at least one support structure.

[0091] Another object of the invention is to provide a thermal therapydevice that can substantially heat deep regions of tissue from the siteof therapy, such as with respect to spinal joints at least about 4 mm, 7mm, or even 10 mm from the site of therapy.

[0092] Another object of the invention is to provide therapeutic levelsof thermal therapy to tissue within relatively short durations of energydelivery, though over relative long-term duration of overall therapy.

[0093] Another object of the invention is to direct therapeutic energyinto targeted tissues from remote locations within the body, such as inor around joints, without substantially harming closely adjacenttissues, such as nerves, vessels, or other tissues not intended to betreated.

[0094] Another object of the invention is to focus energy into targetedregions of tissue within the body.

[0095] Another object of the invention is to enhance cellular functionsin certain tissue structures so as to provide a therapeutic effect.

[0096] Another object of the invention is to enhance drug delivery intoremotely located body tissues, such as within or around joints such asspinal joints.

[0097] Another object of the invention is to treat chronic back pain.

[0098] Another object of the invention is to treat chronic arthritis.

[0099] Another object of the invention is to locally enhance thedelivery, permeability, or cellular uptake related to certaintherapeutic compounds delivered within the spine and other joints.

[0100] Accordingly, one aspect of the invention is an ultrasound energydelivery system for providing long term treatment to a region of tissueassociated with a skeletal joint. The system includes a long-termimplantable ultrasound treatment assembly with an ultrasound transducer,and a skeletal joint delivery assembly that is adapted to deliver theultrasound treatment assembly into the body with the ultrasoundtransducer positioned at a location within the body associated with theskeletal joint. The ultrasound treatment assembly is adapted to providelong-term delivery of a therapeutic level of ultrasound energy from thelocation and into the region of tissue.

[0101] According to one mode of this aspect, a controller is providedthat is adapted to couple with and control the ultrasound transducer,and that also a long-term implant that is adapted to be implanted withinthe body of the patient. In one embodiment, the controller includes apower source, which may in a further regard be rechargeable such as arechargeable battery. In a further variation, the power source isadapted to be recharged by exposure to a magnetic field across a skinbarrier of the patient.

[0102] According to further modes, the controller includes one or moreof a microprocessor, a monitoring assembly, and/or a data storagesystem.

[0103] In another mode, the controller is adapted to communicate acrossthe patient's skin barrier via wireless communications system so as toprovide telemetry with respect to the ultrasound therapy.

[0104] In another mode, the system further comprises an externalassembly that is adapted to communicate with the controller via wirelesssignals so as to receive telemetry with respect to the ultrasoundtherapy.

[0105] According to another aspect of the invention, a long-termimplantable ultrasound controller is provided that is adapted to controlultrasound energy delivery from a long-term implantable ultrasoundtreatment assembly. In one mode, the controller is adapted to operatethe ultrasound treatment assembly according to a set of operatingparameters adapted to stimulate bone growth. In a further embodiment ofthis mode, the set of operating parameters comprises: a transmissionpower level between about 0.1 to about 1 W/cm2, and about 1.5 MHz, andat about 1 kHz repetition, and with burst intervals between about 100 toabout 200 micro-seconds. In another embodiment, the set of parametersfurther includes: total aggregate time of ultrasound delivery is betweenabout 10 to 30 minutes per day for at least one day of long-termultrasound treatment.

[0106] According to another mode, the controller is adapted to operatethe ultrasound treatment assembly according to a set of operatingparameters adapted to enhance drug delivery therapy to the tissue at thelocation. In one embodiment of this mode, the set of operatingparameters includes: transmission power between about 0.5 to about 2W/cm2, operating frequency between about 5 to about 12 MHz, andcontinuous wave delivery. In a further embodiment, the set of parametersfurther comprises: aggregate time of ultrasound delivery between about 5to about 60 minutes per day over at least one day of long-termultrasound treatment.

[0107] In another mode, the controller is adapted to operate theultrasound transducer according to the following set of ultrasoundoperating parameters: transmission power between about 1 to about 30W/cm2, transmission bursts lasting between 50 to 200 microseconds,repetition between bursts between about 1 Hz to about 5 kHz, and atultrasound operating frequencies between about 0.5 to about 15 MHz.

[0108] In another mode, the controller is adapted to operate theultrasound transducer at operating frequencies between about 12 to about15 MHz.

[0109] In another mode, the controller is adapted to operate theultrasound transducer so as to provide thermal therapy in addition toacoustic nervous stimulation.

[0110] In another mode, the controller is adapted to operate theultrasound treatment assembly according to a set of ultrasound operatingparameters adapted to stimulate nervous impulses at the location.

[0111] According to one embodiment of this mode, the set of operatingparameters includes: pulsed ultrasound delivery over periods of lessthan or equal to about 70 microseconds, and operating frequency of about5 MHz.

[0112] In another mode, the controller is adapted to operate theultrasound treatment assembly according to a set of ultrasound operatingparameters adapted to accomplish at least one of: regenerate peripheralnerves, repair pseudarthrosis and bone fractures, stimulate bone growth,and stimulate osteogenesis with respect to repairing fractures.

[0113] In one embodiment of this mode, the set of ultrasound operatingparameters includes: transmission power of about 0.5 W/cm2, operatingfrequency of about 1.5 MHz, treatment interval durations of betweenabout 5 to about 25 minutes per day for at least one day over along-term treatment regimen. In a further variation, the set ofoperating parameters further includes a total period of therapy of aboutfour weeks.

[0114] In another mode, the set of ultrasound operating parametersincludes: ultrasound transmission at about 0.5 W/cm² aggregate dailytreatment of about 15 minutes per day for at least one day over along-term treatment regime.

[0115] Another aspect of the invention is a skeletal joint therapydevice and includes a long-term implantable thermal treatment assemblywith an energy emitter. The thermal treatment assembly is adapted to beimplanted at a location within a body of a patient. The energy emitteris adapted to follow a long-term protocol for energy delivery into aregion of tissue associated with a skeletal joint, such that the thermaltreatment assembly is adapted to heat tissue up to a distance of atleast 4 mm from the energy emitter to a temperature of at least 75degrees C., and is adapted to heat tissue up to a distance of at leastabout 7 mm from the energy emitter to a temperature of at least about 55degrees C., and is adapted to heat tissue up to a distance of at leastabout 10 mm from the energy emitter to a temperature of at least about45 degrees C.

[0116] In a highly beneficial mode of this aspect, the thermal treatmentassembly includes an ultrasound transducer.

[0117] In another mode, the device further comprises a long-termimplantable controller that is adapted to be coupled to and controloperation of the thermal treatment assembly according to the long-termprotocol and according to a set of operating parameters.

[0118] Another aspect of the invention is a long-term implantableultrasound thermal treatment system, and includes a long-termimplantable ultrasound treatment assembly with an ultrasound transducer,and a long-term implantable coupling probe having a elongate body with aproximal end portion and a distal end portion. The distal end portionhas a proximal section with a longitudinal axis, a distal section with adistal tip, and a bend between the proximal and distal sections. Theultrasound treatment assembly is located along the distal section of thedistal end portion and extending at an angle from the proximal section.The distal end portion is adapted to be implanted within the body of amammal by manipulating the proximal end portion such that the ultrasoundtreatment assembly is positioned at a location associated with a regionof tissue to be treated. The proximal end portion is also adapted to beimplanted within the body with the distal end portion implanted with theultrasound treatment assembly at the location. The ultrasound treatmentassembly is adapted to follow a long-term therapeutic protocol ofultrasound energy delivery into the region of tissue from the locationwithin the body.

[0119] Another aspect of the invention is a long-term implantableultrasound thermal therapy system with a long-term implantableultrasound heating assembly with an ultrasound transducer and that isadapted to be implanted within a body of a mammal with the ultrasoundtransducer positioned at a location such that the ultrasound transduceris adapted to deliver a ultrasound energy into a targeted region oftissue in the body from the location. Also includes is a long-termultrasound therapy control system that is adapted to be coupled to theultrasound heating assembly. The long-term implantable ultrasoundtherapy control system is adapted to be coupled to and control operationof the ultrasound heating assembly while it is implanted at the locationaccording to a long-term ultrasound thermal therapy protocol.

[0120] Another aspect of the invention is a long-term directionalultrasound spinal thermal therapy system that includes a long-termimplantable ultrasound delivery assembly with a directional ultrasoundtransducer that is adapted to be positioned at a location associatedwith a spinal joint and to deliver a directed, therapeutic amount ofultrasound energy from the location and to a region of tissue associatedwith the spinal joint.

[0121] Another aspect of the invention is a long-term implantableskeletal joint ultrasound delivery system with a long-term implantableultrasound treatment assembly with an ultrasound transducer and acoupling member. The ultrasound delivery assembly is adapted to beimplanted within a body of a mammal with the ultrasound transducerpositioned at a location within the body associated with a skeletaljoint. The ultrasound transducer is adapted to deliver a therapeuticamount of ultrasound energy to a region of tissue associated with theskeletal joint via the coupling member and according to a long-termultrasound treatment protocol.

[0122] Another aspect of the invention is a long-term implantableultrasound thermal therapy system that includes a long-term implantableultrasound heating assembly that is adapted to be implanted at alocation within a body of a mammal so as to deliver ultrasound energyinto a region of tissue in the body from the location. This system alsoincludes a control system that is adapted to be coupled to theultrasound heating assembly and to control operation of the ultrasoundheating assembly according to a long-term ultrasound thermal therapyprotocol and such that a region of tissue being heated by the ultrasoundheating assembly exceeds a temperature of at least about 70 degrees C.

[0123] Another aspect of the invention is an ultrasound thermal therapysystem with a long-term implantable ultrasound heating assembly that isadapted to be implanted within a body of a patient and to couple with anultrasound controller from the location, and also with a curvilinearultrasound transducer having a concave surface with a radius ofcurvature around a reference axis such that ultrasound energytransmitted therefrom converges into a region of tissue at a targetlocation.

[0124] Another aspect of the invention is a method for providinglong-term, invasive treatment for a medical condition associated with askeletal joint within a body of a patient. This method aspect includesdelivering a therapeutic level of ultrasound energy to a region oftissue associated with the joint from a location within the body of thepatient and according to a long-term ultrasound therapy protocol.

[0125] Another aspect of the invention is a method for providinglong-term, invasive treatment for a medical condition associated with askeletal joint within a body of a patient. This method aspect includesdelivering sufficient energy to a region of tissue associated with theskeletal joint that is sufficient to necrose nociceptive nerve fibers orinflammatory cells in such tissue region without substantially affectingcollagenous structures associated with the skeletal joint and accordingto us of a long-term energy delivery implant and according to along-term energy delivery therapeutic protocol.

[0126] Another aspect of the invention is a method for providinglong-term, invasive treatment to a region of tissue associated with anintervertebral disc in a body of a patient. This method aspect includesimplanting a long-term ultrasound transducer implant at a locationwithin the body such that a therapeutic level of ultrasound may becoupled from the transducer to the tissue and according to a long-termultrasound therapy protocol.

[0127] Other method aspects of the present invention with respect toproviding long term tissue therapy via long-term implants includevarious long-term implantable adaptations of other aspects elsewhereherein described.

[0128] Another aspect of the invention is an implantable spinal thermaltherapy system with a spinal delivery system and a spinal thermaltherapy device. The spinal delivery system is adapted to deliver athermal therapy assembly of the spinal thermal therapy device to alocation within the body such that the energy may be coupled to a regionof tissue associated with a vertebral joint.

[0129] Another aspect of the invention is an ultrasound energy deliverysystem for treating a region of tissue associated with a skeletal joint,and includes an ultrasound treatment assembly with an ultrasoundtransducer; and a skeletal joint delivery assembly. The skeletal jointdelivery assembly is adapted to deliver the ultrasound treatmentassembly into the body with the ultrasound transducer positioned at alocation within the body associated with the skeletal joint. Theultrasound treatment assembly is adapted to deliver a therapeutic levelof ultrasound energy from the location and into the region of tissue.

[0130] Another aspect of the invention is a skeletal joint thermaltherapy device with a thermal treatment assembly on the distal end of adelivery member. The thermal treatment assembly includes an energyemitter. The distal end portion is adapted at least in part to deliverthe thermal treatment assembly into a body of an animal with the energyemitter positioned at a location such that the energy emitter is adaptedto deliver energy into a region of tissue associated with a skeletaljoint. The thermal treatment assembly is adapted to heat tissue up to adistance of at least 4 mm from the energy emitter to a temperature of atleast 75 degrees C., and is adapted to heat tissue up to a distance ofat least about 7 mm from the energy emitter to a temperature of at leastabout 55 degrees C., and is adapted to heat tissue up to a distance ofat least about 10 mm from the energy emitter to a temperature of atleast about 45 degrees C.

[0131] Another aspect of the invention is an ultrasound thermaltreatment system with an ultrasound treatment assembly with anultrasound transducer on a distal end portion of a rigid delivery probe.The probe's distal end portion has a proximal section with alongitudinal axis, a distal section with a distal tip, and a bendbetween the proximal and distal section. The ultrasound treatmentassembly is located along the distal section of the distal end portionand extending at an angle from the proximal section. The distal endportion is adapted to be delivered into the body of an animal bymanipulating the proximal end portion externally of the body and suchthat the ultrasound treatment assembly is positioned at a locationassociated with a region of tissue to be treated. Moreover, theultrasound treatment assembly is adapted to deliver a therapeutic levelof ultrasound energy into the region of tissue from the location withinthe body.

[0132] Another aspect of the invention is an ultrasound thermal therapysystem with an ultrasound heating assembly with an ultrasound transducerand a therapy control system coupled to the ultrasound heating assembly.The ultrasound heating assembly is adapted to be delivered into a bodyof an animal with the ultrasound transducer positioned at a locationsuch that the ultrasound transducer is adapted to deliver a therapeuticamount of ultrasound energy into a targeted region of tissue in the bodyfrom the location. The therapy control system is adapted to controloperation of the ultrasound heating assembly such that a substantialportion of the region of tissue being heated by the ultrasound heatingassembly does not exceed a maximum temperature of at least about 70degrees C.

[0133] Another aspect of the invention is a directional ultrasoundspinal thermal therapy system with an ultrasound delivery assembly. Theultrasound delivery assembly has a directional ultrasound transducerthat is adapted to be positioned at a location associated with a spinaljoint and to deliver a directed, therapeutic amount of ultrasound energyfrom the location and to a region of tissue associated with the spinaljoint.

[0134] Another aspect of the invention is a skeletal joint ultrasounddelivery system with an ultrasound treatment assembly with an ultrasoundtransducer and a coupling member. The ultrasound delivery assembly isadapted to be delivered into a body of a mammal with the ultrasoundtransducer positioned at a location within the body associated with askeletal joint. The ultrasound transducer is adapted to deliver atherapeutic amount of ultrasound energy to a region of tissue associatedwith the Another aspect of the invention is an ultrasound thermaltherapy system with an ultrasound heating assembly and a control system.The ultrasound heating assembly is adapted to be positioned at alocation within a body of a mammal so as to deliver ultrasound energyinto a region of tissue in the body from the location. The controlsystem is adapted to couple to the ultrasound heating assembly and tocontrol operation of the ultrasound heating assembly such that a regionof tissue being heated by the ultrasound heating assembly exceeds atemperature of at least about 70 degrees C.

[0135] Another aspect of the invention is an ultrasound thermal therapysystem with a an ultrasound heating assembly located along the distalend portion of a delivery member. The ultrasound heating assembly has acurvilinear ultrasound transducer having a concave surface with a radiusof curvature around a reference axis that is transverse to thelongitudinal axis of the distal end portion.

[0136] Another aspect of the invention is a method for treating amedical condition associated with a skeletal joint within a body bydelivering sufficient energy to a region of tissue associated with theskeletal joint that is sufficient to necrose nociceptive nerve fibers orinflammatory cells in such tissue region without substantially affectingcollagenous structures associated with the skeletal joint.

[0137] Another aspect of the invention is a method for treating a regionof tissue associated with an intervertebral disc in a body of an animalby delivering an ultrasound transducer to a location within the bodysuch that a therapeutic level of ultrasound may be coupled from thetransducer to the tissue.

[0138] Another aspect of the invention is a method for treating ananimal by delivering energy to a region of tissue associated with thespine, wherein such energy delivery is between about 10 and about 300equivalent minutes at 43 degrees C.

[0139] Another aspect is a method for invasively treating a medicalcondition associated with an intervertebral disc within a body of animalby delivering a therapeutic level of ultrasound energy to a region oftissue associated with an intervertebral disc from a location within thebody of the patient.

[0140] Another aspect of the invention is a method for treating medicalcondition associated with a joint between two bony structures in a bodyof an animal by delivering an ultrasound transducer to a location withinthe patient's body associated with the joint; and emitting ultrasoundenergy from the transducer at the location so as to provide atherapeutic effect to at least a portion of the joint.

[0141] Another aspect of the invention is a method for treating ananimal by introducing an ultrasound transducer into a body of theanimal; positioning the ultrasound transducer at a location within theanimal that is adjacent to at least one of an annulus fibrosus of anintervertebral disc, a nucleus pulposus of the intervertebral disc, or avertebral body associated with a spinal joint in the body; and emittingultrasound energy from the ultrasound transducer at the location.

[0142] Another aspect of the invention is a method for providingultrasound energy delivery within a body of an animal by introducing anultrasound transducer into a body of a patient; positioning theultrasound transducer at a location within the patient that is within atleast one of an annulus fibrosus of an intervertebral disc, a nucleuspulposus of the intervertebral disc, or a vertebral body associated witha spinal joint in the body; and

[0143] emitting ultrasound energy from the ultrasound transducer at thelocation.

[0144] Another aspect of the invention is a method for treating apatient by ultrasonically heating a region of tissue associated a spinaljoint to a temperature between about 45 to about 90 degrees Fahrenheitfor sufficient time to cause a therapeutic result in the tissue.

[0145] Further objects and advantages of the invention will be broughtout in the following portions of the specification, wherein the detaileddescription is for the purpose of fully disclosing preferred embodimentsof the invention without placing limitations thereon.

BRIEF DESCRIPTION OF THE DRAWINGS

[0146] The invention will be more fully understood by reference to thefollowing drawings which are for illustrative purposes only:

[0147]FIG. 1A shows a side perspective view of an illustration of atypical human spine for treatment according to the systems and methodsof the invention.

[0148]FIG. 1B shows an exploded, cross-sectioned side view of the regiondepicted as 1B in FIG. 1A, and shows an intervertebral disc between twoadjacent vertebral bodies.

[0149]FIG. 2 shows an angular perspective view of a transverselycross-sectioned intervertebral disc in relation to adjacent spinalstructures.

[0150]FIG. 3A shows an angular perspective view of an ultrasonicintervertebral disc therapy system according to the invention, andincludes a partially segmented view of an ultrasound treatment device, aschematic view of an ultrasound drive system, and an angular perspectiveview of an introduction device, respectively, of the system.

[0151]FIG. 3B shows a longitudinal side view taken along lines 3B-3B inFIG. 3A.

[0152]FIG. 3C shows a transverse cross-sectioned view taken along lines3C-3C in FIG. 3A.

[0153]FIG. 4 shows a transverse cross-sectioned view of the distal endportion of another ultrasound treatment device of the invention with adifferent support structure under the ultrasound transducer of thedevice than the support structure shown in FIG. 3C.

[0154]FIG. 5A shows a slightly angled side view of the distal endportion of another ultrasound treatment device according to theinvention, and also shows a schematic view of a guide wire included inthe system.

[0155]FIG. 5B shows a cross-sectioned side view of the device takenalong lines 5B-5B in FIG. 5A.

[0156]FIG. 6A shows a slightly angled side view of an ultrasoundtransducer component assembly for use in the distal end portion ofanother ultrasound treatment device according to the invention.

[0157]FIG. 6B shows a cross-sectioned transverse view taken along lines6B-6B in FIG. 6A.

[0158]FIG. 6C shows a schematic cross-sectioned side view of analternative ultrasound transducer component assembly within anultrasound treatment device according to the invention versus that shownin FIG. 6B.

[0159]FIG. 6D shows an angular perspective view of a semi-sphericaldisc-shaped transducer for use according to a further embodiment of theinvention.

[0160] FIGS. 7A-F show a top perspective view of a laterallycross-sectioned intervertebral disc during respectively sequential modesof operating the ultrasound treatment system for intervertebral disctherapy according to the invention.

[0161] FIGS. 8-9 show alternative modes of operating an ultrasoundtreatment device according to the invention for treating differentrespective regions of an annulus fibrosus of a disc from within thenucleus and according to a posterior-lateral approach into the disc.

[0162]FIG. 10 shows an alternative mode of operating an ultrasoundtreatment device according to the invention using an anterior approachto treat a posterior wall region of the annulus fibrosus of a disc fromwithin the nucleus of the disc.

[0163] FIGS. 11-13 show alternative modes of operating an ultrasoundtreatment device for treating different respective regions of an annulusfibrosus of a disc from externally of the annulus fibrosus and withoutentering the nucleus, wherein FIGS. 11 and 13 show a posterior-lateralapproach to right lateral and posterior wall regions of the annulus,respectively, and FIG. 12 shows an anterior approach to a left lateralwall region of the annulus.

[0164] FIGS. 14A-B show plan perspective views of the distal end portionof another ultrasound treatment device of the invention during variousmodes of operation, wherein FIG. 14A shows a straight configuration forthe device, and FIG. 14B shows two modes of angular deflection for thedistal end portion of the device.

[0165]FIG. 14C shows a top perspective view of another ultrasoundtreatment device of the invention with a distal ultrasound treatmentsection that is adapted to be rotated about a hinge point for minimallyinvasive treatment of intervertebral discs and other spine or jointdisorders.

[0166]FIG. 15A shows a plan perspective view of the distal end portionof another ultrasound treatment device of the invention having apredetermined shape and operative region for ultrasound delivery thatcorresponds to particular desired approaches and ultrasound therapy tocertain specified regions of tissue associated with an intervertebraldisc.

[0167]FIG. 15B shows a perspective view of another ultrasound treatmentdevice having a similar shape to that shown in FIG. 15A, but having adifferent operative region for ultrasound delivery corresponding todelivering invasive therapy to a different desired region of arespective intervertebral disc.

[0168]FIG. 16 shows a perspective view of another ultrasound treatmentdevice having a different unique shape and operative region forultrasound delivery corresponding to delivering invasive therapy to adifferent desired region of a respective intervertebral disc.

[0169]FIG. 17A shows a top view of an ultrasound treatment deviceassembly with transducers inside of an outer cooling jacket that isinterfaced with a fluid circulation pump to actively cool thetransducers.

[0170]FIG. 17B shows a top view of another partially cross-sectionedultrasound treatment device assembly similar to that shown in FIG. 17A,except showing the cooling fluid to circulate from within the ultrasoundtransducer device and into the surrounding sheath.

[0171]FIG. 18A shows an x-ray picture of an explanted disc being treatedaccording to one aspect of the invention, and shows various data pointsalong temperature monitoring probes inserted along certain desiredlocations for monitoring across the disc.

[0172]FIG. 18B shows a graph of temperature vs. time for an ultrasoundheating study in an explanted cadaver spine disc, and shows curves fortissue depths of 1 mm, 4 mm, 7 mm, and 10 mm away from the directionalheating transducer.

[0173]FIG. 19 shows a typical modulus versus applied stress plotaccording to a study performed in Example 2, and shows results before(solid line) and after (dashed line) heat treatment at 85° C., andindicates the following biomechanical parameters: change in modulus atthe inflection point (MI), change in modulus at 150 kPa (M150), andchange in residual stress at the inflection point (RSI).

[0174]FIG. 20 shows a typical stress-strain plot before (solid line) andafter (dashed line) treatment at 85° C., and shows for each cycle anupper line indicating the loading phase, and a lower curve indicatingthe unloading phase.

[0175]FIG. 21 shows graphs (a)-(e) that variously represent respectivechanges in certain tissue parameters that were observed after variedheat treatments.

[0176]FIG. 22 shows various light microscopy photographs of varioustissue samples, and includes bright light (left panel) and polarizedlight (right panel) microscopy of specimens treated, and shows pictures(a, b) for samples intact at 37° C.; pictures (c, d) for intact samplesat 85° C.; and pictures (d, e) representing excised at 85° C.

[0177]FIG. 23 shows a schematic side view of a distal end portion of anexternal directional ultrasound thermal treatment (“ExDUSTT™”) device ofthe invention incorporating a directional, focused ultrasound emitterassembly that is adapted for external use adjacent to an intervertebraldisc.

[0178]FIG. 24 shows an illustrated side view of a partiallycross-sectioned ultrasound spinal treatment assembly similar to thatshown in the ExDUSTT device shown in FIG. 23, and shows the assemblyduring one mode of use in treating a region of an intervertebral discassociated with a spinal joint.

[0179]FIG. 25 shows a plan view of a distal end portion of a furtherExDUSTT embodiment that incorporates a substantially rigid, pre-shapedprobe device platform.

[0180]FIG. 26 shows a plan view of a distal end portion of anotherExDUSTT device embodiment that incorporates a substantially flexible,catheter device platform according to another embodiment of theinvention.

[0181]FIG. 27A shows a longitudinally cross-sectioned view of a distalend portion of an ExDUSTT device on a rigid probe platform similar tothat shown in FIG. 25, and shows a substantially compliant elastomericballoon over a curvilinear ultrasound transducer.

[0182]FIG. 27B shows a transverse cross-sectioned view through anultrasound transducer mounting region of the ExDUSTT device shown inFIG. 27A.

[0183]FIG. 28A shows a longitudinally cross-sectioned view of a distalend portion of another EXDUSTT device on a rigid probe platform that isalso similar to that shown in FIG. 25, except with a substantiallynon-compliant pre-formed balloon over the curvilinear ultrasoundtransducer.

[0184]FIG. 28B shows a transverse cross-sectioned view through anultrasound transducer mounting region of the ExDUSTT device shown inFIG. 28A.

[0185]FIG. 29A shows a transverse cross-sectioned view of a distal endportion of another ExDUSTT device on a polymeric catheter deliverychassis similar to that shown in FIG. 26, and shows a substantiallycompliant elastomeric balloon over a transversely aligned, curvilinearultrasound transducer.

[0186]FIG. 29B shows a transverse cross-sectioned view through anultrasound transducer mounting region of the EXDUSTT device shown inFIG. 29A.

[0187]FIG. 30A shows a transverse cross-sectioned view of a distal endportion of another EXDUSTT device on a catheter delivery platformsimilar to that shown in FIG. 29A, except with an axially aligned,curvilinear ultrasound transducer within a substantially compliantelastomeric balloon.

[0188]FIG. 30B shows a transverse cross-sectioned view through anultrasound transducer mounting region of the ExDUSTT device shown inFIG. 30A.

[0189] FIGS. 31A-B show two respective graphs for acoustic efficiencyand acoustic output power, respectively, for one exemplary workingembodiment of a rigid probe EXDUSTT device similar to that shown in FIG.25.

[0190] FIGS. 32A-B show two respective graphs for acoustic efficiencyand acoustic output power, respectively, for one exemplary workingembodiment of a catheter-based ExDUSTT device similar to that shown inFIG. 26.

[0191]FIG. 33 shows a schematic drawing of an ultrasound heatingassembly portion of a catheter-based EXDUSTT device similar to thatshown in FIG. 26 superimposed over an X-ray picture of theintervertebral disc to illustrate one experimental set-up to evaluatethe device, and also shows superimposed reference numbers designatingcertain monitored temperatures at various locations within the discduring one mode of treatment.

[0192] FIGS. 34A-B show two respective graphs of temperature monitoredover time at various thermocouples locations 105(C)-109(C) during tworespective in-vivo thermal therapy treatments in an intervertebral pigdisc using a catheter-based ExDUSTT device similar to that shown in FIG.26 and according to an experimental set-up similar to that shown in FIG.33.

[0193]FIG. 35 shows two, respective ExDUSTT devices of pre-shaped, rigidprobe construction similar to that shown in FIG. 25, except the devicesshown are constructed according to different size embodimentsincorporating ultrasound transducers having varied respective widths of2.5 mm and 3.5 mm, respectively.

[0194] FIGS. 36A-B show top and angular perspective views, respectively,of certain power output profile across the face of the 2.5 mm widetransducer shown in FIG. 35A.

[0195] FIGS. 37A-B show top and angular perspective views, respectively,of certain power output profiles across the face of the 3.5 mm widetransducer shown in FIG. 31B.

[0196]FIG. 38 shows an X-ray picture of a top view of an ex-vivoexperimental arrangement similar to that shown schematically in FIG. 33,except showing a directional ultrasound heating assembly of a workingembodiment for a probe-based ExDUSTT device such as shown in FIG. 25positioned for desired heating of an intervertebral disc according toone modes of use, and shows various thermocouple probes within the discto monitor experimental temperatures.

[0197]FIG. 39 shows an exploded view of the same Ex-DUSTT intervertebraldisc treatment arrangement shown for the 3.5 mm probe-like ExDUSTTdevice in FIG. 38, and shows monitored temperature values at variousrespective locations along the axial and radial temperature probesduring one relatively high temperature mode of use with active coolingat 0 degrees C.

[0198]FIG. 40 shows a graph of temperature vs. time for the varioustemperature probes according to the thermal therapy arrangement shown inFIG. 39.

[0199]FIG. 41 shows a graph of temperature monitored along the 5 mm and10 mm deep axial temperature sensor probes and the radial temperaturesensor probes shown within the intervertebral disc and during treatmentwith the probe-based ExDUSTT with the 3.5 mm wide transducer shown inFIG. 38, and according to an ex-vivo study performed with activetransducer cooling at 0 degrees C.

[0200]FIG. 42 shows the same exploded view of the experimentalarrangement shown in FIG. 39, except shows thermocouple valuescorresponding to a relatively low temperature mode of operation withroom temperature cooling.

[0201]FIG. 43 shows a similar graph of temperature vs. time as thatshown in FIG. 40, except with respect to data measured according to thearrangement illustrated for FIG. 42.

[0202]FIG. 44 shows another graph of certain temperature vs. transducerposition results similar to the graph shown in FIG. 41, except showingresults according to the mode of operation also variously illustrated inFIGS. 42-43.

[0203]FIG. 45 shows a similar exploded X-ray picture to that shown inFIGS. 39 and 42, except showing thermocouple values according to arelatively low temperature mode of operation using a 3.5 mm widetransducer and cooling at 0 degrees C.

[0204]FIG. 46 shows another temperature vs. time graph, except withrespect to the arrangement also illustrated in FIG. 45.

[0205]FIG. 47 shows a graph of temperature vs. thermocouple positionresults according to the thermal therapy arrangement illustrated inFIGS. 45 and 46.

[0206]FIG. 48 shows another exploded X-ray picture of the same ExDUSTTarrangement, except according to use of a 2.5 mm wide transducer withrelatively low temperature heating mode and cooling at 0 degrees C.

[0207]FIG. 49 shows another temperature vs. time graph for the EXDUSTTheating arrangement illustrated in FIG. 48.

[0208]FIG. 50 shows another temperature vs. thermocouple position graphfor a 2.5 mm curvilinear ExDUSTT ex-vivo disc treatment using 0 degreeC. cooling and relatively low temperature mode of operation.

[0209]FIG. 51 shows another exploded X-ray picture, except withthermocouple values corresponding to use of a 2.5 mm transducer ExDUSTTdevice at a relatively low temperature mode of use with room temperaturecooling.

[0210]FIG. 52 shows a temperature vs. time graph according to theExDUSTT mode of therapy also illustrated in FIG. 51.

[0211]FIG. 53 shows a temperature vs. thermocouple position graph forthe modes of ExDUSTT therapy illustrated in FIGS. 51 and 52.

[0212]FIG. 54 shows a perspective view of an internal directionalultrasound thermal therapy system (“InDUSTT™”) that includes a spinaldisc delivery probe and an InDUSTT device that fits within the spinaldisc delivery probe.

[0213]FIG. 55A shows a plan view of a schematic representation of aninternal ultrasound thermal spine therapy device according to anotherembodiment of the invention.

[0214]FIG. 55B shows an exploded view taken at region B shown in FIG.55A, and shows enhanced detail of various aspects of the ultrasoundheating assembly along the distal end portion of the InDUSTT systemaccording to a further feature of that embodiment.

[0215]FIG. 55C shows a transverse cross-sectioned view taken along lineC-C in FIG. 55A.

[0216] FIGS. 56A-B show respective X-ray pictures of the distal endportion of an InDUSTT system similar to that shown in FIGS. 54-55Bpositioned within an intervertebral disc during in-vivo thermal spinaltreatments according to certain modes of the invention.

[0217]FIG. 57 shows a table providing thermal dosimetry data collectedduring certain modes of in-vivo operation for various workingembodiments of an InDUSTT system similar to that shown in FIGS. 54-55Band providing therapeutic ultrasonic heating at various temperaturemodes of powered operation corresponding to C2/3, C3/4, C4/5, and C5/6intervertebral sheep discs, respectively.

[0218]FIG. 58 shows various X-ray pictures of the placement of theInDUSTT transducer within the C2/3, C3/4, C4/5, and C5/6 intervertebraldiscs corresponding to the results provided in the table in FIG. 57.

[0219]FIG. 59A shows a graph of temperature vs. time during InDUSTTheating of a C3/4 intervertebral disc according to a relatively hightemperature mode of use, and shows curves for various respectivethermocouple probe positions.

[0220]FIG. 59B shows a graph of temperature vs. time using the sameInDUSTT device as that used for creating the data shown in FIG. 59A,except shows results according to a relatively low temperature mode ofuse in a C4/5 intervertebral disc location.

[0221]FIG. 59C shows a graph of temperature monitored at varioustemperature sensor positions during 10 minute InDUSTT heating, and showscurves for results in two separate intervertebral discs each heated witha different one of two separate InDUSTT systems of the invention.

[0222]FIG. 60 shows another table providing thermal dosimetry datacollected during modes of in-vivo operation for various workingembodiments of a directly coupled InDUSTT system providing therapeuticultrasonic heating from within C2/3, C3/4, and C4/5 intervertebral discsof a sheep.

[0223]FIG. 61 shows various respective X-ray pictures of certaintransducer placements for the directly coupled InDUSTT during in-vivospinal disc thermal therapy at the C2/3, C3/4, and C4/5 intervertebralsheep discs corresponding to the similarly designated rows of dataillustrated in the table of FIG. 60.

[0224]FIG. 62A shows a graph of temperature vs. time corresponding tothe C2/3 disc treatment shown in FIG. 61 and according to a relativelyhigh temperature mode of use.

[0225]FIG. 62B shows a graph of temperature vs. time corresponding tothe C3/4 disc treatment shown in FIG. 61, and according to a relativelylow temperature mode of use.

[0226]FIG. 62C shows a graph of temperature monitored at varioustemperature sensor positions during 10 minute directly coupled InDUSTTheating, and shows curves for thermal treatment results at both deadsectors and active sectors of the transducer in the C2/3 disc atrelatively high temperature power level, and at similar locations in theC3/4 disc at the corresponding, relatively low temperature power level.

[0227]FIG. 62D shows a graph of accumulated thermal dose versustemperature sensor position for the 10 minute treatments at the C2/3 andC3/4 discs at the relatively high and low temperature power levels,respectively.

[0228]FIG. 63 shows another table providing thermal dosimetry datacollected during modes of in-vivo operation for various workingembodiments of a catheter cooled InDUSTT system providing ultrasonicheating from within C2-3, C3-4, C4-5, and C5-6 intervertebral discs of asheep.

[0229]FIG. 64 shows various respective X-ray pictures of certaintransducer placements for the catheter cooled InDUSTT during in-vivothermal spinal disc therapy at the C2-3, C3-4, C4-5 and C5-6intervertebral discs corresponding to the similarly designated rows ofdata illustrated in the table of FIG. 63.

[0230]FIG. 65A shows a graph of the relatively high temperature,catheter cooled InDUSTT therapy of the C2/3 disc as monitored overmultiple temperature sensors along first and second temperature probespositioned within the disc.

[0231]FIG. 65B shows a temperature vs. time graph of the relatively lowtemperature mode of operation for the catheter cooled InDUSTT therapy inthe C3/4 disc and as monitored over multiple temperature sensors alongfirst and second temperature monitoring probes positioned within thedisc.

[0232]FIG. 65C shows a temperature vs. time graph of the relatively hightemperature, catheter cooled InDUSTT therapy of the C5/6 disc asmonitored over the multiple temperature sensors along first and secondtemperature monitoring probes positioned within the disc.

[0233]FIG. 65D shows a graph of temperature monitored at various axialpositions relative to the transducer during 10 minute catheter cooledInDUSTT heating, and shows curves for thermal treatment results atvarious locations in the C2/3 disc at relatively high temperature powerlevel, in the C3/4 disc at relatively low temperature power level, andC5/6 disc at relatively high temperature power levels.

[0234] FIGS. 66-68 show respective schematic views of differentembodiments for a long-term implantable ultrasound spinal therapy devicesystem according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0235] Referring more specifically to the drawings, for illustrativepurposes the present invention is intended to provide thermal treatmentto spinal joints, and in particular intervertebral discs as illustratedin FIGS. 1A-2, as embodied in the apparatus shown and characterized byway of the various modes of operation with respect to certain intendedanatomical environments of use variously throughout FIGS. 3-65D. It willbe appreciated that the apparatus may vary as to configuration and as todetails of the parts, and that the method may vary as to the specificsteps and sequence, without departing from the basic concepts asdisclosed herein.

[0236] As an initial introduction, various respective aspects, modes,embodiments, variations, and features of the invention are herein shownand described, both broadly and in variously increasing levels ofdetail. Each provides individual benefit, either in its own regard, orin the ability to provide enhanced modes of operation and therapy by wayof combinations with other aspects or features. Moreover, their variouscombinations, either as specifically shown or apparent to one ofordinary skill, provide further benefits in providing useful healthcareto patients.

[0237] In one regard, two illustrative ultrasound spinal thermal therapyprobe configurations are described for applying thermal (heat) therapyor ultrasound (US) exposure to tissues within the spine or other joints.Heat at high temperatures and thermal doses can shrink tissues, changethe structural matrix, generate physiological changes and/or kill cells.Heat at relatively lower temperatures and US exposure can generatepermeability changes or changes in the cellular transport/metabolismthat increase effectiveness or deposition of certain pharmaceuticalagents. The heat or US can be delivered with the present invention in ahighly controlled fashion to selected tissue regions in order to exploitthese physiological effects for therapeutic purposes. Ultrasoundapplicators may achieve more precise targeting or heating control notpossible with current RF and Hot Source techniques. For soft tissue orbone surfaces within the spine or other joints, the high temperatureexposure can be used to shrink tissue impinging on nerves, re-structureand possibly strengthen mechanical properties of the disc or jointmaterial, destroy abnormal or undesirable cells or tissue, destroynerves responsible for pain, seal leaks from the disc annulus/nucleus,joint capsules, etc. Novel ultrasound applicators and treatmentmethodologies are thus herein shown and described which allow for theinterstitial insertion or laparoscopic or arthroscopic placement ofthese applicators within or upon targeted tissue to receive suchtreatments or prophylaxis.

[0238] As will be further developed by reference to the Figures below,one exemplary type of such an applicator and treatment methodologyprovides a segmented array of tubular, sectored tubular, plate,hemispherical, or portions of cylinders (e.g. convex) with linearcontrol of US exposure or heating via power level adjustments andangular control of US exposure or heating via directionalcharacteristics of the applicators. (e.g. angularly directive with aninactive zone). These transducers are mounted over a guidewire lumen ortube or structure to facilitate placement, wires, and/or coolingstructures. Thermometry sensors can be placed directly on thetransducer/tissue or applicator/tissue interface. Internal cooling viagas or liquid or external cooling via an outer plastic sheath orcatheter can be accomplished, though may not be necessary in manyinstances. These can be inserted within the disc or laparoscopicallyplaced against the target tissue or directed toward the target tissue.Acoustic gain and temperature regulation of applicator surface(s) canhelp control distance of heated regions and effects from the applicatorsurface. Frequency and depth of focus can be selected to control heatingpattern, and time can be varied to control heating effects anddistribution. Some of the device and method embodiments provided hereinmay incorporate various features similar to those previously disclosedsuch as in U.S. Pat. No. 5,620,479 to Diederich, though in manyinstances will be modified specifically for heating within the specialenvironment of use within or around intervertebral discs or otherjoints.

[0239] Another illustrative type of applicator according to the presentinvention incorporates a segmented array similar to that describedabove, but using concave sections of cylindrical or tubular transducersor spherical or semi-spherically focused transducers. The outer diameter(OD) of the tubes used to form such transducers are much larger than theapplicator diameter for the tubes—the sectors activated are a small arcof the tube they otherwise would be a part of. Thus, a line ofconvergence, e.g. focus, is produced at depth over a small arc angle,producing an intense US exposure or heating pattern which isapproximately the same length as the tubular segment transducer emittingthe US, though very narrow (e.g. 1-5 degrees) in the angular dimension.The length and number of segments can be varied in either applicatortype described here for introduction purposes (or elsewhere herein), andmay be a single transducer versus an array. These applicators can alsohave internal cooling or external cooling as described above and furtherdetail with respect to the particular embodiments below. The applicatorscan be inserted within the disc or laparoscopically placed against thetarget tissue or directed toward the target tissue. Acoustic gain andtemperature regulation of applicator surface can help control distanceof the heated region and effects from the applicator surface. Furtherapplicable features may by incorporated from other prior disclosures,such as U.S. Pat. No. 5,391,197 to Burdette et al. disclosing prostatetherapy devices and methods, and may be modified to suit the particularneeds for the present invention. Frequency and depth of focus can beselected to control heating pattern, and time can be varied to controlheating effects and distribution.

[0240] The various embodiments herein described have applications inother soft and/or hard tissue sites and body parts where ultrasoundexposure, high temperature, low temperature, or combination effects aredesired.

[0241] Each type of applicator can be designed with or without coolingballoons, distendable (e.g. compliant and/or elastomeric) or pre-shaped(e.g. substantially non-compliant with relatively fixed inflation sizeand shape), and symmetric or asymmetric shapes are considered. Thedevices' respective chasses may be substantially stiff, e.g. rigidprobes, or flexible. They may further be either implantable within thetarget tissue, or be used on surface contact. They may be delivered on aguidewire rail platform, through pre-shaped insertion or placementguides, or have their own steerability or deflectability. For spinaltreatments, they may be placed surgically following for example aposterior approach, or laparoscopic/arthroscopic lateral/anteriordirected to the spinal joint for treatment.

[0242] Treatment methodologies contemplated include implanting thedevices within or positioning them next to the target tissue forheating, such as for example inserted into a disc or joint capsule, orplaced outside of the disc or joint.

[0243] Directivity and cooling aspects, when incorporated, protectsensitive non-targeted tissue, which is highly beneficial for example inspinal applications protecting spinal nerves. Applicators hereindescribed are repositionable according to various modes to controlangular thermal profile according to their directed energy delivery. Inone example for further illustration, a specially adapted spinal discinsertion apparatus is adapted to deflect an applicator being deliveredtherethrough into the spinal disc from an angle. Other specialprocedures and tools are also herein described to align the applicatorswith target areas of tissue such as with respect to spinal joints andintervertebral discs in particular.

[0244] Though many different configurations, sizes, shapes, anddimensions are contemplated consistent with the overall intent to meetthe various objects of the invention, exemplary devices may be providedwith outer diameters between about 1.2 to about 3 mm, though may be upto 5 mm in some instances, deliverable as desired to spinal joint areasfrom 18 gauge.

[0245] Insertion techniques into tissue to be treated may progressaccording to several examples. In one mode, a relatively stiff (e.g.sufficient to support the intended use), pre-shaped guidewire is usedwhich may be with or without memory metal alloy such as nickel titaniumfor example. The guidewire is inserted under fluoroscopy and positionedin an annulus fibrosus or posterior annulus, avoiding the nucleus of thedisc. An applicator of the relatively more flexible variety is theninserted over the guidewire and into position. In another regard, arelatively stiff (e.g. sufficient support) pre-shaped insertion toolguides the applicator with a sharp tip into the annulus from outsidewithout requiring the guidewire (though they may be used inconjunction). Similar insertion techniques may be used for thermometryplacement, if desired. Such delivery tool may thus be multi-lumened tointegrate both placements (e.g. applicator and temperature probes)simultaneously for better positioning, etc.

[0246] Contact therapy techniques of operation may also proceedaccording to a variety of modes. An arthroscopic approach is suitablefor many applications, such as for example as follows. Internal tipdeflection may be used to align (e.g. steer) the applicator with oralong the outside of an annulus—e.g. similar to certain intracardiaccatheters (such as mapping or ablation devices). Such may be integratedto a steerable catheter. The device according to these modes may beplaced lateral or posterior behind the disc and nerves, or ventral. Thedevice is aligned with the disc, the region is targeted and then treatedwith directional thermal therapy.

[0247] Various of the components herein described for the variousembodiments may be provided together, or may be provided separately. Forexample, implements for providing streaming liquid or balloon to protecttissue from transducer conductive heating may be an integral part of therespective applicator, or may be separate as an accessory.

[0248] The applicators and respective insertion and/or guidance toolsherein described may be further adapted to be compatible with magneticresonance imaging for real time monitoring of the procedure. Otherimaging modalities may also be used for positioning, monitoring, thermalmonitoring, lesion assessment, real-time monitoring of coagulation, etc.This includes ultrasound monitoring.

[0249] Further to the ultrasound aspects of the various embodiments, useof such energy modality provides temperature elevation as one mode ofcreating an intended effect, but also provides other non-thermal effectson tissues, such as for example drug activation, etc., such as forexample to treat arthritis at joints where the applicator is being used.

[0250] It is to be appreciated that the invention is in particular welladapted for use in treating intervertebral disc disorders of the spine,such as at spinal joints, and in particular at an intervertebral disc 1shown in various relation to surrounding spinal structures of a spinaljoint in FIGS. 1A-2. In particular, as will be further developed below,disc disorders associated with chronic lower lumbar back pain are to bebeneficially treated according to the invention. However, it is to beappreciated that other disorders of the discs in particular, and ofother joints (e.g. hips, knees, shoulders, etc.) may also be treatedaccording to the device systems and methods herein shown and described.For example, other regions of the vertebrae will be beneficially treatedwith invasive ultrasound delivery according to the invention in order topromote bone growth, such as for example to assist in the healing ofinjuries or bone-grafts. Areas between the vertebral bodies, or thespinal processes, for example, may be treated with US application fromthe present devices and according to the methods as herein shown anddescribed. In particular, regions such as graft between inner bodiesthrough nucleus; anterior inner body fusion; posterior lateral fusionare contemplated. Ultrasound energy may be delivered with collagenmatrixes or autograft/allograft materials to bone.

[0251] A typical intervertebral disc 1 such as shown in FIGS. 1A-2generally includes an annulus fibrosus 2 that surrounds a nucleuspulposus 3 along a plane that lies between two adjacent vertebrae 8,9,respectively, that are located above and below, also respectively, disc1 along the spine. More specifically, disc 1 lies between two the twocartilaginous endplates 8 a, 9 a that border two adjacent vertebralbodies 8 b, 9 b of vertebrae 8,9, respectively.

[0252] As will be further developed below, an ultrasound treatmentdevice according to the invention may be located in various places inand around a disc 1. A variety of such locations is shown for thepurpose of illustration at locations a-d in FIG. 1B, wherein device 11is shown: within the middle of the nucleus at location a; along theborder between the nucleus 3 and the annulus 2 such as shown at proximalwall at location b; in the wall of the annulus itself, as shown forexample at location c; or outside of the disc 1 around the outerperiphery of annulus 3, as shown at location d. Moreover, the device mayalso be delivered into and around bony structures associated with thespinal joint, such as for example shown at locations e, f, g, or h inFIG. 1B. Such positioning may be accomplished for example by drilling abore into the vertebral body from a posterolateral approach through anassociated pedicle, as shown in shadow at location E in FIG. 2, or via amore lateral approach as shown directly into the body at location F inFIG. 2. Such positioning and heating within bone structures associatedwith the joint may be in particular useful in one regard for treatingbone cancer, destroying nociceptive nerves, stimulating growth or druguptake (e.g. low thermal dose applications). Either the vertebral bodyitself may the target for heating, or the end plate, or the disc fromsuch location. A further particular useful application of this istreatment of osteoporotic back pain.

[0253] As shown in particular in FIG. 2, disc 1 also has a shape similarto a “kidney”-shape with a concave curvature along a proximal wall 4that borders the spinal cord (not shown), as well as along oppositeanterior wall 5. Right and left anterior walls 6,7 are generallycharacterized by a more acute radius of curvature than posterior andanterior walls 4,5. As will be further developed below, each of theseuniquely located and anatomical wall regions may be selectively treatedwith localized therapeutic ultrasound energy according to the system andmethod of the present invention. In general, intervertebral discs (withrespect to the lumbar region associated with lower back pain) aretypically 30 mm wide (e.g. laterally from right wall 6 to left lateralwall 7, about 20 mm front-back, e.g. anterior wall 5 to posterior wall4); and approximately 10 mm tall, e.g. from end plate 8 a to endplate 9a. Accordingly, the devices herein shown and described are to beparticularly adapted to operate within this general description of theintended environment of use within intervertebral discs.

[0254] As will be appreciated by the description below of the variousmodes of operating the ultrasound treatment system of the invention,treatment of the annulus fibrosus 2 from within the nucleus may beachieved via various approaches. In particular, regions A and B shown inFIG. 2 correspond to right and left anterior approaches, whereas regionsC and D correspond to right and left posterior-lateral approaches aroundright and left vertebral prostheses 8 c, 8 d, respectively

[0255] Multiple ultrasound probe configurations are herein described forapplying thermal (heat) therapy or ultrasound (US) exposure to tissueswithin the spine in particular, though other joints such as knee, hip,etc. are contemplated. It is to be appreciated that the two specificprobe configurations shown and described provide highly beneficialembodiments, though they are exemplary and other configurations,improvements, or modifications according to one of ordinary skill basedupon this disclosure in view of the known art are contemplated.

[0256] In any event, heat produced according to the present invention athigh temperatures and thermal doses can shrink tissues, change thestructural matrix, generate physiological changes, and/or kill cellswithin the targeted region of tissue associated with a disc. Heat at lowtemperatures and US exposure can generate permeability changes orchanges in the cellular transport/metabolism that increase effectivenessor deposition of certain pharmaceutical agents. The heat or US can bedelivered with this technology in a highly controlled fashion toselected tissue regions in order to exploit these physiological effectsfor therapeutic purposes.

[0257] Ultrasound applicators may achieve a degree of precise targetingor heating control generally not possible with previously disclosed RF,plasma ion, or heat source techniques. In addition, ultrasound energyactually penetrates surrounding tissues, rather than according to othermodes (e.g. RF and laser) that heat the closest tissues the hottest andallowing conduction therefrom in a diminishing temperature profile curvewith distance away. For soft tissue or bone surfaces within the spine orother joints, high temperature exposure by use of the invention is usedto shrink tissue impinging on nerves, re-structure and possiblystrengthen mechanical properties of the disc or joint material, destroyabnormal or undesirable cells or tissue, destroy nerves responsible forpain, and seal leaks from the disc annulus/nucleus, joint capsules, etc.

[0258] In particular to disc applications, three general goals areintended to be achieved according to use of the present invention: (1)collagen associated with the annulus fibrosus may be reorganized toreshape the annulus; (2) nerve ingrowth in and around the annulus ornucleus may be killed; or (3) inflammatory cells around areas of injuryor otherwise penetrating areas in or around a disc may be killed orablated. In particular with respect to causing nerve damage, this mayinclude regions of the annulus itself, at the endplates, usually islocated posteriorly, and rarely but at times may be within the region ofthe nucleus itself. In any event, such nervous ingrowth is typicallyrelated to structural disc damage that is identified e.g. in a discogramand therefore predicted to be where pain/nerve treatment should bedirected.

[0259] In one particular non-limiting application, either or both ofnerve and inflammatory cells are necrosed by US delivery withoutachieving sufficient heating to denature or weaken, or to denature butnot weaken, or to reshape the disc annulus. This is possible using thedevices and methods of the invention herein described at levels ofenergy delivery between about 10 to about 300 EM43 deg C. (e.g. may befrom 1 to 60 min at between about 42 deg C. and about 45 deg C.). Wherecollagen denaturation, modification, or reshaping is desired, energydelivery from the ultrasound devices herein described may be frombetween about 55 deg C. to about 85 deg C. for between about 10 sec toabout 30 min.

[0260] The novel ultrasound applicators and treatment methodologiesherein disclosed allow for the interstitial insertion or laparoscopic orarthroscopic placement of these applicators within or upon targetedtissue, in particular with respect to intervertebral discs.

[0261] One particularly beneficial embodiment of the invention is shownat ultrasound treatment system 10 in FIGS. 3A-C. This system 10 includesan ultrasound device 11, ultrasound drive system 40, and intervertebraldisc delivery assembly 50.

[0262] Device 11 is shown to couple proximally to an a proximal endportion (not shown) that generally includes a handle (not shown) that isadapted to couple to ultrasound drive system 40, which includes anultrasound actuator 41. Drive system 40 may be operated empirically,such that a predetermined delivery of energy is achieved at a desiredlevel known to produce a desired result. Or, external therapy monitoringmay be employed during treatment, e.g. MRI, CT, fluoroscopy, X-ray,discogram, or PET in order to control energy delivery and determineappropriate levels and time duration for a particular case. Thesemonitoring modalities may be effective prior to treatment in order toidentify the area of concern to be treated, which may impact the choiceof particular device to be used as provided according to the embodimentsherein. Still in a further alternative embodiment, a treatment feedbackdevice 42, such as a temperature monitoring system, may be incorporatedin a feedback control system, as shown in FIG. 3A.

[0263] Device 11 is also adapted to be delivered to the desired locationfor treatment through delivery assembly 50 and therefore has a lengthcorresponding to length L of delivery assembly 50 that is adapted foruse in standard access procedures for intervertebral disc repair. Forposterior-lateral approaches, such as for example in order to invade thenucleus 3 through posterior-lateral sites B or C shown in FIG. 2,delivery assembly 50 is typically a spinal needle of about 18 Gauge.Accordingly, the length for device 11 may be about 30 cm long, with acorresponding outer diameter for device 11 adapted to fit within such aneedle, generally less than about 3 mm, generally between about 1 andabout 3 mm, typically between about 1.2 and 3 mm. However, other sizesmay be realized for applications not requiring delivery throughsize-limiting delivery assemblies such as spinal needles, and up to orgreater than 5 mm OD is realizable (e.g. in particular for applicationsoutside of the disc nucleus or within the annulus). For anteriordelivery such as at sites A or B shown in FIG. 2, delivery assembly 50may be minimally invasive delivery device such as an arthroscope orlaparoscopic assembly.

[0264] Device 11 is of a type that contains a linear array of segmentedtransducers 16 that are adapted to provide selective, localizedultrasonic heating via radial, collimated energy delivery in tissueadjacent to the array. The particular device 11 of the presentinvention, including corresponding elements such as transducers 16located thereon, are generally smaller and more flexible than elsewherepreviously described for other linear array transducer devices. Inaddition, fewer transducers 16 are typically required for treating thegenerally smaller regions of the intervertebral discs as contemplatedherein. These substantial modifications are believed to significantlyenhance the controllability and performance of ultrasound therapy withinthe unique (and often dangerous) anatomy of an intervertebral disc.Otherwise, the basic components for segmented, linear array transducerdevice 11 may be similar to those previously described in U.S. Pat. No.5,620,479, which has been previously incorporated by reference above.

[0265] Referring more specifically to FIGS. 3A through 4, an ultrasoundapplicator 11 of the invention preferably includes a cylindrical supportmember such as a tube, conduit or catheter 12 which may be compatiblefor adjunctive radiation therapy of the spine such as according toremote afterloaders and standard brachytherapy technology. Sincecatheter 12 includes a coaxial longitudinal inner lumen 14, a source ofradiation, a drug or a coolant can be inserted therein, as well asguidewires, deflection members, stylets, etc., according to modifiedembodiments elsewhere herein described. One highly beneficial embodimentfor example uses a polyurethane or other similar polymer that is of asoft, low modulus type according to uses as contemplated herein withinthe sensitive intervertebral discs and elsewhere along the spine andrelated, highly sensitive nervous tissues. Where direct access to thedesired treatment location is possible without risk of damaging soft,sensitive tissues around the spine, a more rigid support may be used,and may even include a thin-walled stainless steel hypodermic tubing orstiff conduits (though shapes may be important as further developedbelow).

[0266] Catheter 12 is coaxially disposed through a plurality of tubularpiezoceramic transducers 16 which are spaced apart and electricallyisolated as shown, thus forming a segmented array of tubular ultrasoundtransducers which radiate acoustical energy in the radial dimension.Transducers 16 may be formed from a variety of materials as has beenpreviously disclosed. Transducers 16 may have an outer diameter betweenabout 0.5 to about 6 mm, though with respect to energy therapy fromwithin the nucleus 3, is more typically between about 0.5 mm and about1.5 mm.

[0267] It is preferred that the wall thickness for transducers 16 besubstantially uniform in order to generate uniform acoustic patternswhere such energy delivery is desired. Further to conjunctive radiationtherapy (e.g. spinal tumor therapy), the transducer material ispreferably stable when exposed to typical radiation sources.

[0268] The frequency range of the transducers will vary betweenapproximately 5-12 MHz depending upon the specific clinical needs, suchas tolerable outer diameter, depth of heating, and inner catheter outerdiameter. Inter-transducer spacing is preferably approximately 1 mm orless. Those skilled in the art will appreciate that, while threetransducers 16 are shown in FIGS. 3A-B, the number and length oftransducers can be varied according to the overall desired heatinglength and spatial resolution of the applicator and depth of penetrationdesired. This may vary for example for devices 11 intended to treatalong the entire length of posterior wall 4 of disc annulus 2, versus alateral wall 6,7 thereof, versus the anterior wall 5. Even the desiredlength along a given one of these regions may vary depending upon theparticular patient, or even within a given patient depending upon aparticular region of the spine being treated (e.g. lower discs along thespine increase in size). Therefore, a kit of devices 11 having variedlengths and sizes for the array of treatment transducers 16 iscontemplated according to such variances. Transducers 16 are also shownto be substantially cylindrical for the purpose of illustration, andwhich design may be desired where uniform heating around thecircumference of the device 11 is desired. However, as developed below,the highly selective tissue therapy typically desired within and aroundintervertebral discs may require in many cases more radial selectivityaround the device 11, as further developed below.

[0269] Each transducer 16 is electrically connected to actuator 41 ofdrive assembly 40, which is typically an RF current supply. Thiselectrically coupling is achieved via separate pairs of signal carryingwires 18, such as 4-8 mil silver wire or the like, soldered directly tothe edges of the transducer surface to form connections 20 a, 20 b. Onewire in the pair is connected to the edge of transducer 16 at its outersurface, while the other is connected to the edge of transducer 16 atits inner surface, although other connection points and modalities arealso contemplated. Each wire 18 is routed through the center of thetransducers between the outer wall of catheter 12 and the inner wall ofthe transducer 16, as can be seen in FIG. 3B, and from there to theconnection point through the spaces between the individual transducerelements.

[0270] In order to ensure that each transducer 16 in the array is keptcentered over catheter 12 while still maintaining flexibility and notimpending transducer vibration, a plurality of spacers 22 are disposedbetween the transducers and catheter 12. These spacers 22 may takevarious forms as previously described. For the particularly smallerdesigns herein contemplated for spinal applications, a “spring-groundlead” comprising 3-4 mil stainless steel wire or the like wound to forma coaxial spring may be placed between a transducer 16 and an electrodedouter surface of inner catheter 12 where such coil is soldered directlythereto. Such electroded outer surface may be a common ground for alltransducers 16.

[0271] As previously disclosed, transducers 16 are preferably“air-backed” to thereby produce more energy and more even energydistribution radially outwardly from device 11. To ensure suchair-backing and that the transducers 16 are electrically andmechanically isolated, a conventional sealant 24 as previously describedis injected around exposed portions of catheter 12, wires 18, andspacers 22 between transducers 16. Sealant 24 serves multiple functionsin this application, as has been previously described.

[0272] As a means for monitoring temperature of tissue surrounding thetransducers 16, and to provide for temperature control and feedbackwhere desired, a plurality of small (e.g. 25.4 um) thermocouple sensors26, such as copper-constantan or constantan-maganin fine wire junctions,are placed along the outer surface of each transducer at points whichare approximately one-half of the length of the transducer, andconnected to individual temperature sensing wires 28 which run alongone-half of the length of the transducer 16 and then through the spacebetween catheter 12 and the transducers 16. A conventional acousticallycompatible flexible epoxy 30 such as has been described is then spreadover the transducers, thereby embedding the temperature sensors. Theepoxy coated transducers are then sealed with an ultra thin walled (e.g.about 0.5 to about 3 mil) tubing 32 that may for example be a heatshrink tubing such as polyester or the like. Or, the epoxy coatedtransducers may otherwise covered, as is known. Heat shrink tubing 32extends beyond the area over transducers 16 and covers substantially thelength of device 11. To support tubing 32 in such extended area, afiller 33 of chosen composition (preferably flexible) is placed aroundcatheter 12 and between it and tubing 32.

[0273] According to the present embodiments and those elsewhere hereinshown and described, a cooling system may be included, which has beencharacterized to increase heating efficiency by about 20-30% versusnon-cooled embodiments. In addition, as shown in FIG. 4, standoffs 34may be used to support transducers 16, which are preferably flexible andmay be an integral part of catheter 12.

[0274] For spinal disc therapies herein contemplated, device 11 isgenerally designed to be sufficiently flexible to be delivered in asubstantially straight configuration through delivery device 50, andthereafter be adapted to assume a configuration appropriate fordelivering energy along a length corresponding to an interface betweenthe linear array of transducers 16 and the desired region of tissue totreat. This flexibility may be modified according to various differentmodes elsewhere herein described in order to achieve appropriatepositioning and shape conformability used in a particular case.

[0275] In one particularly beneficial further embodiment shown variouslyin FIGS. 5A-B, device 11 is modified from the previous embodiment ofFIGS. 3A-4 such that inner support catheter, similar to catheter 12 inFIGS. 3A-4, provides a through lumen 13 that is adapted to slideablyreceive a guidewire 60 therethrough. Guidewire 60 includes a stiffproximal end portion and either a shaped or shapeable, more flexibledistal end portion 62. According to this guide wire-based embodiment forsystem 10, guidewire 60 is adapted to be placed within the desiredregion of treatment by steering and advancing the shaped distal endportion 62 with manipulation of proximal end portion 61 externally of apatient's body. Device 11 along the array of treatment transducers 16 issufficiently flexible to track over guidewire 60 in order to bepositioned for treatment along the desired treatment region. Guidewire60 may be of a shape memory type, or may be designed according to manyother previous guidewire disclosures. Moreover, device 11 may be adaptedto receive and track over guidewire 60 over substantially the length ofdevice 11, also known as “over-the-wire”, or may be of a “rapidexchange” or “monorail”-type wherein guidewire 60 exits proximally fromdevice 11 at a port along device 11 that is distal to the most proximalend of device 11.

[0276]FIG. 5A also shows the linear array of transducers 16 to be of thesegmented type, wherein each linear location for a transducer 16corresponds to two opposite transducer regions 16 a, 16 b that may beindependently or alternatively actuated for energy delivery. This allowslocalization of US energy along only one radial aspect surroundingdevice 11. Particular designs and methods incorporating linear array ofsegmented or partially activated US transducer regions is disclosed inU.S. Pat. No. 5,733,315 to Burdette et al., which has been previouslyincorporated herein above. It is to be appreciated herein that eachtransducer segment 16 a or 16 b is in effect an independently actuatabletransducer, though shown and described as sub-parts of an overalltransducer 16 for illustrative simplicity. Corresponding transducerregions 16 a may be all actuated simultaneously along the array, withoutactuating the opposite regions 16 b, in order to ablate along a lengthonly along one radial aspect of device 11 corresponding to actuatedregions 16 a. Or, the other regions 16 b may be actuated without regions16 a emitting US energy. The device of FIG. 5A provides thisselectivity, which may be useful for treating different regions of adisc annulus as further discussed below.

[0277] Various different shaft structures may be appropriate for housingthe corresponding functional components of a device 11 according to theembodiment of FIG. 5A, though one particular cross-section is shown inFIG. 5B for illustration. Due to the radially segmented aspect of thetransducer array of this embodiment, the number of actuatable transducerelements corresponding to a given length of the array is doubledcompared to the earlier embodiment (e.g., each linear region is splitinto two radial regions). Therefore, twice the number of electrode leads18 and thermocouple leads 28 must be housed. The cross-sectioned,multi-lumen tubing 12A shown in FIG. 5B therefore has a plurality ofsurrounding lumens 14 surrounding a central guidewire lumen 13. This isadapted to give an organized shaft structure for adapting a proximal pinconnector to interface with drive and control system 40, as well asuniform flexibility in multiple planes to enhance delivery and positioncontrol in use.

[0278] Device 11 as illustrated by the FIG. 5A embodiment may includetransducers 16 having many different geometries that may be customizedfor a particular energy delivery profile along the transducer array.Examples include tubular (e.g. FIGS. 3A-4), sectored tubular (e.g. FIG.5A), and also as further examples planar or plate, hemispherical, orportions of cylinders (convex), depending upon the desired energydelivery for a particular application. Further to the FIG. 5Aembodiment, a distinct radial region of a transducer location along thearray may be rendered completely inoperative for US delivery, such asfor example in order to protect against delivery into sensitive tissuessuch as the spinal cord. In any event, according to the variousembodiments, device 11 may be adapted for linear control of US exposureor heating via power level adjustments and angular control of USexposure or heating via directional characteristics of transduceremitters 16 (e.g., angularly directive with an inactive zone).

[0279] A further embodiment shown in FIGS. 6A-C further providessemi-hemispherically shaped transducers 16 that are essentially flippedto have an opposite radial orientation relative to the radius of device11 as compared to otherwise similar transducer sectors 16 a,b in FIG.5A. More specifically, transducer segments 16 a,b each have theirconcave surfaces 17 facing outwardly from device 11. This is believed toallow for a focused US signal to be emitted therefrom to a focal pointor depth in relation to device 11 that is controlled by the radius ofcurvature R for the corresponding transducer. Such an arrangement mayinclude two radial sides of linearly spaced transducers, e.g. 16 a,b asshown in FIGS. 6A-B. Or, device 11 may be adapted to house a single suchtransducer segment 16, as shown in FIG. 6C, which limits the radialemission choices to one region around the device periphery, butincreases the design real estate and options for device 11 to house thisunique transducer configuration. In any event, the applicator device 11may be repositioned to control angular thermal profile. Where angularcontrol is of important necessity (such as treatment immediatelyadjacent spinal column), device 11 may be designed to be in particulartorqueable from outside the body in order to rotate the radially focusedtransmission with the shaft, such as via use of metal reinforcements ortubular members, or in general composite shaft designs such as wire orbraid reinforcements.

[0280] As elsewhere herein shown and described, device 11 along the USpath from transducer 16 generally includes an ultrasonically translucentmedium, such as a fluid. Acoustic gain and temperature regulation ofapplicator surface can help control distance of heated region andeffects from applicator surface. Frequency and depth of focus can beselected to control heating pattern, and time can be varied to controlheating effects and distribution.

[0281] The segmented array of FIG. 6C can use many different types oftransducers 16, such as for example concave sections of cylindrical ortubular transducers or spherical or semi-spherically focusedtransducers. The OD of the tubes used to form the transducer shown inFIG. 6C is much larger than the diameter D for device 11 that supportsthe transducer 16. The transducer sectors are a small arc; thus, a linefocus is produced at depth over a small arc angle, producing an intenseUS exposure or heating pattern which is approximately the same length asthe tubular segment, but very narrow in the angular dimension, which canbeneficially be as narrow as from about 1 to about 10 deg., preferablyas narrow as from about 1 deg. to about 5 deg. The length and number ofsegments can be varied.

[0282] Referring to the particular embodiment shown in FIG. 6D, aconical or semi-spherical disc-shaped transducer 16 is shown whichfocuses energy not only radially along a length of the correspondingtransducer, but instead focuses along the entire surface of thedisc-shape. Therefore such shaped transducer more precisely and denselyfocuses and localizes the energy being delivered into a very smallregion of tissue. While an array of such shaped disc transducers 16 iscontemplated, the focused pattern may create energy gaps betweenadjacent elements—therefore this design may be more applicable toprecise treatment in one area by one transducer, which may be followedby moving the transducer, either together with or along the supportingdevice 11 to another location to be treated.

[0283] As previously mentioned above, the embodiments of FIGS. 6A-D, inaddition to the other embodiments contemplated herein, can cooled eitherexternally or internally, an can be inserted within the disc orlaparoscopically placed against the target tissue or directed toward thetarget tissue. Acoustic gain and temperature regulation of applicatorsurface can help control distance of heated region and effects fromapplicator surface. Frequency and depth of focus can be selected tocontrol heating pattern, and time can be varied to control heatingeffects and distribution. Other examples of ultrasound array techniquesfor adjusting the selectivity of ultrasound transmission from a deviceare disclosed in U.S. Pat. No. 5,391,197, which has been previouslyincorporated by reference above; the various embodiments of thatdisclosure are contemplated in combination with this disclosure withrespect to segmented array of US transducers, where appropriate and asmodified according to this disclosure according to one of ordinaryskill.

[0284] As elsewhere provided herein, the illustrative embodiments andprocedures have applications in many different soft/hard tissue sitesand body parts where ultrasound exposure, high temperature, lowtemperature or combination of effects are desired. Joints in particularare locations where the present invention is well suited for providingtherapy. However, as stated above of particular benefit is use of thepresent invention for treating intervertebral discs.

[0285] Therefore, one example of a method for treating an intervertebraldisc according to the present invention is provided according to varioussequential modes of use shown in FIGS. 7A-F. This procedure for thepurpose of illustration more specifically shows posterior-lateralapproach to treating a posterior wall of an intervertebral disc from alocation within the nucleus. However, because selectivity in disctreatment is so very important, clearly other procedures arecontemplated as will be further developed through other examples below.

[0286] More specifically, according to FIG. 7A a posterior wall 4 ofannulus 2 is observed to require thermal treatment, either due tophysical damage to the annulus 2 structure (e.g. herniation), orotherwise, such as for example innervation with unwanted nervous tissuecausing pain or other inflammatory cells (which may be directly orindirectly related to disc damage such as herniation). As shown in FIG.7A, a sharp, pointed tip 51 of a spinal needle 50 is used in aposterior-lateral approach to puncture through the posterior-lateralregion of the wall of annulus 2. This gives lumenal access throughneedle bore 53 into the nucleus 3 for ultrasound probe delivery.

[0287] As shown in FIG. 7B, a guidewire 60 having a steerable distal tip62 is then advanced through needle bore 53 and into nucleus 3. It iscontemplated that guidewire 60 may be used for many purposes within thenucleus 3, or otherwise in or around disc 1. However, one particularlybeneficial use is shown, wherein guidewire is tracked along proximalwall 4, and then further around the more severe radius along lateralwall 7. This gives a rail along proximal wall 4 along which a highlyflexible device 11 may track for ablation there. This is shown in FIG.7C, wherein ultrasound transducers 16 are of length, size, and locationalong device 11 such that they are positioned over guidewire 60 tocoincide with the area along posterior wall 4 to be treated. Accordingto the embodiment shown in FIG. 7D, only one radial aspect of device 11is actuated for US emission and treatment, which is shown to betransducer segments 16 b in an array on one radial aspect of device 11interfaced with or facing proximal wall 4. Thus US energy is transmittedinto wall 4 to treat that region without substantial treatmentelsewhere.

[0288] After treatment, other regions may be treated by furthermanipulating guidewire 60 and/or device 11 within the nucleus 3 (oroutside of annulus if desired). Once treatment within the annulus iscompleted, device 11 may be withdrawn. In the embodiments shown in FIGS.7E-F, the ultrasound transducers 16 may be used to assist in closing thewound formed at entry site C through annulus, such as by elevating thetemperature in that area sufficient to cause collagen shrinkage to aidin closing that aperture, as shown in FIG. 7F for example. In thisapplication, the entire circumference of device 11 may be activated forUS emission, or if only a radial region is adapted for such emission, itmay be rotated to heat all aspects of the wound aperture to seal it. Inaddition, a sealant may be administered through the distal end of device11 to close the wound, such as at introduction region C, either insteadof or in conjunction with ultrasonic emission from device 11.

[0289] Other regions of disc 1 may also require localized, selectivetherapy with US, and the present invention allows for highly specializedtreatments in the various regions. FIGS. 8 and 9 for example show use ofdevice 11 from the right posterior-lateral approach through site C shownin FIGS. 7A-F, but for treating anterior wall 5 and left lateral wall 7regions, respectively. For the embodiments shown wherein device 11 ishighly flexible for sufficient trackability over guidewire 60, the samedevice may be used for treating the very different areas shown in FIGS.7A-F, FIG. 8 (anterior wall), and FIG. 9 (left lateral wall). However,as shown in comparing FIGS. 7A-F, 8, and 9, different radial regions ofdevice 11 may be activated to treat the respective interfacing wall(where angular specificity is provided, which may not be required thoughoften preferred). In particular, the guidewire trackability of thepresent embodiments provides for highly beneficial flexibility betweenthe ability to treat these very different segments, in particular inview of the generally more significant curvature associated with theanatomy around the lateral wall regions as shown at radius R for lateralwall region 7 shown in FIG. 9.

[0290] For the purpose of further illustration, FIG. 10 shows a device11 according to the invention used to treat a posterior wall 4 of disc1, but according to an anterior approach through a region of anteriorwall 5 adjacent to left lateral wall 7. Again, this may for example be asimilar device as that shown and described with respect to FIGS. 7A-9.

[0291] The devices and methods of the invention are also adapted for usein treating spinal disorders from outside of the annulus 2, thoughpreferably still from an invasive location within the patient's body inorder to provide the necessary and desired amounts of energy at only thehighly localized, target locations. For example, FIG. 11 shows a rightposterior-lateral approach to treat a region of annulus 2 from outsideof disc 1. Because of surrounding tissues, it is highly desired (thoughnot always required), to deliver only highly selective, directed USenergy into only the region of annulus 2 being treated. In particular,truncal nerves often extend along such areas, as well as the spinal cordbeing located not to far away from such region. Therefore, acontrollable, selective array of transducers as shown at transducers 16a radiates only toward the disc annulus 2, whereas the opposite side ofdevice 11 is non-emissive. In fact, this opposite side may beselectively cooled to prevent from thermal heating of the area, and mayinclude sensors to monitor such temperature around that area oppositethe active US treatment zone, such as for example at thermocouples 27shown in FIG. 11.

[0292] For the purpose of further illustration, FIG. 12 also shows UStreatment from outside of a disc 1 according to the invention, butaccording to an anterior approach. FIG. 13 shows still another exteriortreatment modality, however this particular location along the posteriorwall 4 is particularly sensitive as the spinal cord is locatedimmediately adjacent device 11 opposite transducers 16 a and must not beharmed. Therefore, not only the radial emission of energy (either US orthermal heat) from device 11 must be insulated from that radial regioncorresponding to the spinal cord.

[0293] Though guidewire tracking mechanisms provide the illustrativeembodiments for positioning in FIGS. 7A-13, other embodiments arecontemplated. Moreover, positioning of a device 11 may includesimultaneous or sequential positioning of thermometry probes formonitoring of sensitive tissue areas, etc.

[0294] A pre-shaped or otherwise directional introduction/deliverydevice may assist to point a device 11 to a localized area fortreatment, such as shown for example in shadow in FIG. 3A for shaped tip51 for delivery device 50. Such directionality from the delivery device50 may be provided in addition to, or in the alternative to, providingguidewire tracking of device 11 or other additional positioning modesherein discussed. In addition, other positioning control mechanisms maybe incorporated into device 11 itself as follows.

[0295] One particular deflectable tip design is shown for device 11 inFIGS. 14A-B. According to this embodiment, the region of device 11 thatincludes the array of transducers 16 is deflectable to take a variety ofshapes, such as shown in right and left deflection modes around a radiusr in FIG. 14B. Such deflection may be achieved using conventionaldeflection mechanisms, such as for example using an arrangement of oneor more pull-wires integrated into the tip region so that tension causescatheter deflection. In addition, such deflection may be achievedinstead of along a length of an arc, around a pivot point, as shown inFIG. 14C. Such may be achieved in order to achieve different angles forsurgical approaches into the desired treatment areas, such as in oraround intervertebral discs. The transducer elements may be along adeflectable segment that is either round, or may be more planar asdesired.

[0296] Pre-shaped distal regions for device 11 may also provide fordesired treatment of highly unique anatomies. A kit of devices, eachhaving a particular shape is contemplated. Such shapes may be integratedin procedures with or without conjunctively using guidewire tracking.For example, FIG. 15A shows a pre-shaped distal end for device 11 havinga simple distal curve around radius r. The transducers 16 are around theouter radius of such shaped end, and therefore this shape andorientation is suitable for example for treating an anterior wall 5 fromwithin a disc 1 via a posterior-lateral approach, such as for exampleaccording to FIG. 8. A similar shaped end is shown in FIG. 15B, but thetransducers 16 are instead on the inside radius r. This is more suitablefor posterior-lateral approach with posterior wall treatment, such asfor example in FIGS. 7A-F.

[0297] A further beneficial shape and orientation is shown in FIG. 16.Here, an acute bend shown around radius r2 is adapted to correspond tothe more drastically rounded lateral wall regions 6,7 of a disc annulus2 with an energy emission region on the outside of that bend. Anadditional bend region may be highly beneficial, though not alwaysrequired, shown proximally of the distal bend around radius r2 andhaving a less drastic bend, in the opposite direction of r2, shownaround radius r2. This configuration is highly beneficial for treatinglateral wall regions 6,7 from a posterior-lateral approach (e.g. FIG.9), though may be used in the same configuration or slightly modifiedfor anterior approach.

[0298] Though ultrasound transducers and their many benefits forinvasive energy delivery into tissues has been extensively hereindescribed, various of the embodiments further contemplate use with otherenergy sources or treatment modalities, either instead of or inconjunction with ultrasound. Thus, treatment region 16 in FIG. 16 doesnot specifically show individual ultrasound segments as in the otherfigures, for the purpose of illustrating other energy sources ortreatment modalities that my be incorporated thereon and still gain thebenefit of the unique shape provided for inner disc ablation accordingto that figure. Other sources such as electrical (e.g. RF), light (e.g.laser), microwave, or plasma ion may be used. In addition, cryotherapyor chemical delivery may be achieved along the regions variouslydesignated as “transducer 16”, which may be accompanied by othermodifications corresponding therewith, without departing from the scopecontemplated by the embodiments.

[0299] According to the various deflectable or pre-shaped modes, ormodes where energy delivery is limited to only one side of the device,the device 11 is preferably torqueable, such as by integrating into theshaft design a composite of braided fibers or other stiff members. Thisallows for more precise control of the distal tip regions as it deflectsor takes its shape along a plane within the desired area of the body totreat.

[0300] The various embodiments for device 11 above may be adapted toincorporate active cooling, such as circulating cooling fluids within oraround active energy emitting elements such as transducers 16 variouslyshown or described. Such cooling may be integrated into the particulardevice 11, or may be achieved by interfacing the particular device 11inside of or otherwise with another device.

[0301]FIG. 17A shows for example device 11 within an outer jacket 15that may or may not be distendable, as shown in shadow at 15′. Outerjacket 15 is adapted to circulate fluids around transducers 16 andtherefore is interfaced with a circulation pump 70 in an overall system.In an alternative embodiment sharing many common features as FIG. 17A,the device 11 shown in FIG. 17A provides for the cooling fluid to bedelivered through an interior passageway of the interior ultrasounddevice, out the distal tip thereof within the outer jacket 15, and backover the outer surface of the interior device including the transducers16.

[0302] In either the FIG. 17A or 17B embodiments, device 11 may be fixedwithin outer jacket 15, or may be moveable relative to outer jacket 15,or visa versa. Fluids provided in an outer jacket surroundingtransducers 16 according to the invention may also be used beneficiallyfor ultrasound coupling to intended tissues to be treated. This may bein addition to or instead of being used for cooling. In particular, suchcoupling fluids may be provided in a jacket 15 that is conformable, suchthat irregular surfaces to be treated receive uniform energy couplingfrom the assembly. Or, pre-shaped, and symmetric or asymmetric shapes,may be provided as appropriate to provide such coupling. Ultrasoundcoupling may be further achieved by providing a non-liquid couplingmember as a stand-off over a transducer in order to couple thattransducer to the tissue—such as for example a sonolucent coupling gelpad, etc.

[0303] In addition to the various designs for device 11 described abovefor achieving positioning, e.g. guidewire tracking, pre-shaped, ordeflectable, other mechanisms may also be incorporated for accuratepositioning. For example, stiff or flexible distendable member(s) may beincorporated on device 11, e.g. a balloon or expandable cage, thatdistends to a predetermined-shaped (or just generally distends). Thismay help positioning, such as for example where the nucleus 3 is void ofpulposus in order to position the transducers 16 within a balloon at adesired location within the annulus 2. In addition to positioning, sucha member may also be used to aid coupling, tissue deforming, and tissuerepositioning during a treatment procedure.

[0304] As previously discussed, the intervertebral disc applications ofultrasound herein contemplated require high selectivity for US orotherwise thermal therapy due to the presence of highly sensitive,non-targeted tissues in close proximity (e.g. spinal cord and othernerves). Therefore, though heat conduction may not be the intended modeof therapy with transducers 16, their concomitant heating during USsonic wave delivery may cause unwanted damage in either the targeted ornon-targeted tissues. Accordingly, cooled lumens or balloons over thetransducers may be employed to protect such tissues from such heat, ordirectivity of the ultrasound per the embodiments herein described myadequately protect sensitive non-targeted tissue. In the case of anactive cooling mechanism, it is to be appreciated that such mechanismmay be integrated directly onto device 11 that carries the transducers16. Or, a separate co-operating device such as an outer sleeve carryingcooling fluids may be used. Such cooling chamber may be on the side ofthe transducer delivering the targeted US wave, in which case fluid inthe chamber must be substantially sonolucent for efficient energydelivery. In the event the cooling is intended to protect a “back side”of the device only, other fluids may be used.

[0305] Applicators, such as the various embodiments shown for device 11among the FIGS., and insertion tools, e.g. delivery device 50, may beadapted to be MR compatible for real time monitoring of a particularprocedure. Also other imaging modalities may be used instead, or inconjunction with one another, in order to control and optimize the UStreatment procedure, including for example for monitoring positioning,temperature, lesion assessment, coagulation, or otherwise changes intissue structures related to the treatment (e.g. targeted tissue to beheated or adjacent tissues to monitor safety, such as regions of concernto preserve nerves associated with the spinal cord). In fact, US itselfis an energy source that has been widely used for acoustic imaging inand around internal body structures. It is contemplated that imaging USdevices may be incorporated into a device 11 directly, or indirectlyincorporated as a separate cooperating device in system 10, and furtherthat the US treatment transducers 16 herein shown and described may beoperated in imaging modes before, during, or after thermal US therapy isperformed with those same transducers 16.

[0306] In addition to the spine, the device systems and methodsaccording to the embodiments may be used in other regions of the body,in particular other joints. Examples of such regions include knee,ankle, hip, shoulder, elbow, wrist, knuckles, spinal processes, etc. Insuch case, further modifications from the illustrative embodimentsherein provided may be made in order to accommodate the unique anatomyand target tissue regions, without departing from the spirit and scopeof the present invention.

[0307] While the device systems and methods have been herein describedwith respect to treating tissue via US exposure in order to providehyperthermia effects, other non-thermal results may also be intended,either in conjunction with hyperthermia or in the alternative to. Forexample, drug activation and or enhanced drug delivery, such as forexample via enhanced dispersion or cellular permeability or uptake, maybe achieved by delivering certain specific therapeutic dosing of USenergy, as has been well studied and characterized in the art. Suchmethods may for example aid in the treatment for example of arthritis injoints, etc.

[0308] The invention as described herein according to the particularembodiments is highly beneficial for treatment of the body, inparticular joints, and in particular the spine. In general, thesedevices and methods are adapted for such treatment invasively fromwithin the body. However, external applications are contemplated aswell. In addition, treating living bodies according to the invention isbelieved to provide a highly therapeutic result for improved living.Nevertheless, use of the devices and methods as described herein arealso contemplated for conducting scientific studies, in particular withrespect to characterizing tissues in their relation to applied energy.Therefore, “therapeutic” applications may include those sufficient toinduce a measurable change in tissue structure or function, whetherliving or post-mortem, prophylactic or ameliorative, research orclinical applications.

EXAMPLE External Directional Ultrasound Thermal Therapy of CadaverSpinal Discs

[0309]FIG. 18A shows an X-ray photograph of a cadaver intervertebraldisc during invasive ultrasound treatment with a device and methodaccording to the invention as follows. Temperature monitoringmeasurements are shown as overlay dotted lines and numbers over theX-ray.

[0310] An ultrasound probe was provided as follows. Two PZT ultrasoundtransducers were provided on a hypotube, each being 1.5 mm OD×10 mm long(0.012″ wall thickness), and being spaced by about 1 mm. The ultrasoundprobe was inserted within a 13-g Brachytherapy Implant Catheter having a2.4 mm O.D., which is commercially available from Best Industries. Waterat room temperature was circulated through the outer catheter and overthe transducers at about 40 ml/min during ultrasound transmission. Theassembly of the outer catheter with inner transducers and probe wasinserted laterally into a cadaver disc along the border of the nucleuspulposus and posterior wall of the annulus fibrosus. The approximatelocation of the transducers is shown in two rectangles in FIG. 18A.Thermocouple probes were inserted into the disc as shown in the X-ray,and with measurement locations reflected by the sample measurements inthe overlay. The above test sample and instrumentation was placed withina 37 deg C. water bath during testing. Each transducer was run atapproximately 10W power, wherein temperature numbers shown in FIG. 18generally represent temperatures at substantially steady state afteractuating the transducers. Heat generated by the ultrasound probe wassufficient to cause therapeutic effects in surrounding tissues of theannulus and nucleus.

[0311] Another similar study was performed using ultrasound to heat apost-mortem intervertebral cadaver disc using a curvilinear ultrasoundapplicator directly coupled to tissue at 5.4 MHz and 10W power. Atemperature vs. time graph of the results at varied depths from thetransducer surface are shown in FIG. 18B, which shows among otherinformation that temperatures reached 70-85 degrees within 7 mm from thedisc treatment surface and within 5 minutes of treatment.

[0312] As shown in the graph of FIG. 18B, the elevated temperatureachieved at 1 mm from the ultrasound transducer reached: over 45 degreesC. within 90 seconds (1½ minutes); over 70 degrees C. within 120 seconds(2 minutes); over 75 degrees C. in nearly 120 seconds; over 80 degreesC. within 180 seconds (3 minutes); and over 85 degrees C. by about 300seconds (5 minutes).

[0313] Temperatures at 4 mm depth from the transducer reached: 45degrees C. in less than 120 seconds (2 minutes); 55 degrees in close toabout 120 seconds; 65 degrees C. within 150 seconds (2½ minutes); over70 degrees C. within less than 210 seconds (3½ minutes); and over 75degrees C. and still rising by about 240 seconds (4 minutes).

[0314] Temperatures at 7 mm depth from the transducer reached: 45degrees C. by about 120 seconds (2 minutes); 55 degrees C. by about 150seconds (2½ minutes); 60 degrees C. in nearly 180 seconds (3 minutes);65 degrees C. within 240 seconds (4 minutes); and 70 degrees C. within300 seconds (5 minutes).

[0315] Temperatures at 10 mm depth from the transducer reached: 45degrees C. in less than 150 seconds (2½ minutes); 55 degrees C. in lessthan about 210 seconds (3½ minutes); over 60 degrees C. in less than 270seconds (4½ minutes); and slightly less than about 65 degrees C. by 300seconds (5 minutes).

[0316] In another regard, the graph in FIG. 18B also shows thattemperatures above 45 degrees C. were reached within 90 seconds at 1 mm,120 seconds at 4 mm and 7 mm, and 150 seconds at 10 mm depths from thetransducer. Similarly, temperatures of at least 55 degrees C. werereached within about 120 seconds at 1 mm and 4 mm, 150 seconds at 7 mm,and 210 seconds at 10 mm depths. Temperatures of at least 65 degrees C.were reached within less than 120 seconds at 1 mm, 150 seconds at 4 mm,240 seconds at 7 mm depths. Still further, temperatures above 70 degreesC. were reached within 120 seconds at 1 mm, 210 seconds at4 mm, and 300seconds at 7 mm depths. Even further heating to above 75 degrees C. werereached within close to 120 seconds at 1 mm, and 240 seconds at 4 mmdepths.

[0317] Further observation of FIG. 18B in the time domain, in less than150 seconds temperatures at up to 7 mm depth from the transducer reachedat least 55 degrees C. Within about 210 seconds temperatures in tissueas deep as 4 mm deep reached over 70 degrees C., up to 7 mm deep reachedat least 60 degrees C., and up to 10 mm deep is reached over 55 degreesC. Within 270 seconds, temperatures 4 mm deep reached over 75 degreesC., up to 7 mm deep reached over 65 degrees C., and up to 10 mm deepreached over 60 degrees C. In still a further regard, by 300 secondstemperatures up to 7 mm deep reached at least 70 degrees C., and up to10 mm deep reached almost 65 degrees C.

[0318] Upon further comparison of temperatures vs. depth according tothe FIG. 18B graph: temperatures over 60 degrees C. (and for the mostpart up to 65 degrees or more) were achievable up to 10 mm deep;temperatures up to at least 70 degrees C. were achieved up to 7 mm deep;temperatures over 75 degrees were achieved up to at least 4 mm deep; andat 1 mm depth temperatures of over 80 degrees and even 85 degrees wereobserved.

[0319] As will be further developed below and elsewhere herein, suchelevated heating, including at tissues as deep as 4 mm, 7 mm, and insome regards even 10 mm, is a highly beneficial aspect of the presentinvention. For example, other more conventional intervertebral discheating devices, in particular the “IDTT” device elsewhere hereindescribed, have been observed to be limited as to the extent and depthof heating possible.

[0320] For example, according to at least one study observing theheating effects of the “IDTT” radiofrequency electrical heating device(elsewhere herein described) also on cadaveric lumbar spine discsamples, the following observations were made. During intended modes ofuse for internal disc heating, and over treatment times of 17 minutes(1020 seconds), the IDTT devices tested were able to heat only theclosest 1-2 mm of intervertebral disc tissue to temperatures just barelyexceeding 60 degrees, with no tissue of 1 mm depth or greater exceeding65 degrees C. despite reaching 90 degrees C. on the probe itself.Moreover, only tissues within a 7 mm radius of the heating probeexceeded 48 degrees C. during the 17 minute treatment time. Stillfurther thermal dosing was limited such that the maximum predicted depthfor damaging nociceptive fibers infiltrating the discs was believed tobe only within a 6-7 mm radius.

[0321] Accordingly, substantial benefit is gained by using theultrasound treatment device of the present invention to the extent depthof heating and heating to substantial temperatures and within reasonabletimes is desired.

EXAMPLE

[0322] Thermal Therapy of Pre-Stressed Spinal Joints

[0323] This Example provides an abstract summary, introduction, methods,results, and conclusions with respect to a certain group of studiesperformed to evaluate heat-induced changes observed in intervertebraldiscs, related structures such as in particular annulus fibrosus, andthe related biomechanics, in particular with respect to “intact” discs,as follows.

[0324] 1. Abstract.

[0325] The intervertebral disc is considered a principal pain generatorfor a substantial number of patients with low back pain. Thermal therapyhas been disclosed to have a healing effect on other collagenoustissues, and has been incorporated into various minimally invasivetreatments intended to treat back pain. Since the therapeutic mechanismsof thermal therapy have generally been previously unknown, proper dosageand patient selection has been difficult. Thermal therapy in one regardhas been disclosed to acutely kill cells and denature and de-innervatetissue, leading to a healing response.

[0326] The purpose of this study was to quantify the acute biomechanicalchanges to the intact annulus fibrosus after treatment at a range ofthermal exposures and to correlate these results with the denaturationof annular tissue. Intact annulus fibrosus from porcine lumbar spineswas tested ex vivo. Changes in biomechanical properties, microstructure,denaturation temperature, and enthalpy of denaturation before and afterhydrothermal heat treatment (at 37, 50, 60, 65, 70, 75, 80, and 85° C.)were determined. Shrinkage of excised annular tissue was also measuredafter treatment at 85° C. Significant biomechanical changes in theintact annulus were observed after treatment at 70° C. and above, butthe effects were much smaller in magnitude than those observed inexcised tissues. Histological and mDSC data indicated that denaturationhad occurred in intact annular tissue treated to 85° C. for 15 minutes,though such effect was observed to be slight. It is believed based onobservations made that constraints imposed on the tissue by the jointstructure retard changes in properties. These findings have implicationsfor dosing regimens when thermally treating disc tissue.

[0327] 2. Introduction.

[0328] The goals of this study were to: 1) quantify acute biomechanicalchanges to the intact annulus fibrosus induced by a broad range of exvivo thermal exposures; and 2) to correlate these results withdenaturation of annular tissue using modulated differential scanningcalorimetry (mDSC) and histological data.

[0329] 3. Methods.

[0330] a. Mechanical Testing.

[0331] Forty-one spinal motion segments (18 L₁₂, 19 L₃₄, 19 L₅₆)consisting of the intervertebral disc (IVD) and each adjacent vertebralbody were cut from 22 fresh frozen porcine lumbar spines (domestic farmpig weight range: 115-135 lbs). Muscular and ligamentous structures,facet joints, transverse processes, and posterior elements weredissected from the vertebral bodies to isolate the disc. Saline-soakedgauze was wrapped around the discs during preparation to minimizedehydration. Next, the nucleus was depressurized by drilling holes firstthrough the vertebral bodies to the center of the nucleus in thesuperior-inferior direction, and then from the anterior faces of thevertebral bodies to the central hole. Plastic tubing was inserted intothe anterior openings and affixed with cyanoacrylate. The vertebralbodies, anchored with 2.5 mm threaded rod, were embedded into fixationcups using polymethylmethacrylate (PMMA). An alignment bar mated withgrooves in the fixation cups to ensure that the plane of the discremained normal to the vertical loading axis. X-rays (Faxitron CabinetX-Ray System, Hewlett-Packard, McMinnville, Oreg.) were taken of thespecimens in the dorsal-ventral plane after equilibration in a 37° C.saline bath. Disc heights were determined by averaging three caliperreadings from the dorsal-ventral x-rays.

[0332] Specimens were secured in fixation cups, mounted into a hydraulicmaterials testing machine (MTS Bionix 858, Eden Prairie, Minn.), andplaced into a temperature controlled 0.15M saline bath at 37° C. toequilibrate. Saline at bath temperature was also circulated through thecenter of the discs via the tubing attached to the vertebral bodies;this allowed for a more rapid and uniform heat distribution within theannulus.

[0333] Temperatures were measured using two stainless steel thermocoupleneedle probes, one placed in the bath, and one inserted approximatelyhalfway into the anterior annular wall. These fine-needle temperatureprobes were fabricated in-house using 25 micron constantan-manganinthermocouple junctions embedded within a 30 gauge (0.30 mm OD) needle.Superior-inferior x-rays were used to verify proper placement of theannular temperature probe.

[0334] The testing protocol consisted of a 20-minute thermalequilibration at 37° C., a 15-minute heat treatment, and another20-minute equilibration at 37° C. Fast temperature changes werefacilitated by exchanging the saline in the bath with that in areservoir heated to the desired temperature and then maintained withtemperature-controlled circulation. The target temperature (to within7%) was reached within 5 minutes of exchanging the saline. During theequilibrations, the disc stress was maintained at 0 kPa.

[0335] Mechanical testing was performed at 37° C. just prior to heattreatment and again subsequent to heat treatment and re-equilibration at37° C. Testing consisted of nine preconditioning cycles in axialtension-compression (−25 to +150N at 0.25 Hz), followed by one testingcycle to the same limits. The applied load was measured using aprecision force transducer (Load Cell 662, MTS, Eden Prairie, Minn.),and the deformation of the disc was assumed to be the change in distancebetween fixtures, measured using the test system LVDT. Data wascollected every 0.01 seconds during mechanical testing and every 15seconds during heat treatment and equilibration. Heat treatment was toone of the following temperatures: 37 (Controls), 50, 60, 65, 70, 75,80, or 85° C. Five specimens were tested at each treatment temperatureexcept for the 60° C. group that had six specimens.

[0336] After testing, specimens were removed and the discs were cut inthe transverse plane and scanned at a resolution of 600 dpi (CanoScanN656U, Canon, Inc., Costa Mesa, Calif.). Annulus areas were measuredusing imaging software (Scion Image, v. 4.0.2B, Frederick, Md.).

[0337] Two additional experiments were conducted to allow us to explorethe limits of annular thermal response. In the first study, a specimenwas prepared as described above and treated at 85° C. until the thermalcontraction stabilized (within 0.01 mm). For the second study, sectionsof anterolateral annulus were excised from five lumbar discs (2 L₂₃, 3L₄₅) from four different spines and treated at 85° C. using the sameheating protocol as above. X-rays were taken before and after treatment,and changes in circumferential and radial dimensions after heattreatment were measured using digital calipers.

[0338] b. Microstructure

[0339] Tissue samples were excised from 37° C. and 85° C. mechanicaltest specimens, and from an excised specimen treated at 85° C. Sampleswere embedded in paraffin, sectioned in the circumferential plane at 6microns, and stained with HBQ (Hall, 1986). The sections were imaged ona Nikon Eclipse E800 microscope (Nikon, Melville, N.Y.) under brightfield to examine tissue structure, and under polarized light to assesscollagen birefringence.

[0340] c. Modulated Differential Scanning Calorimetry

[0341] Traditional DSC measures the combined effects of reversible andnonreversible heat flow, but the two components can be measuredseparately if the modulated DSC (mDSC) technique is used. mDSC wasperformed on samples of anterolateral annulus fibrosus removed fromfifteen previously treated specimens (Cambridge Polymer Group,Somerville, Mass.). Punches (approximately 10 mg) were removed from thecontrol (37° C.) mechanical test specimens (n=5), mechanical testspecimens treated at 85° C. (n=5), and from the excised annularspecimens treated at 85° C. (n=5). Each sample was placed in 0.1% NaClsolution for 20 minutes, blotted, weighed, and crimped into an aluminumanodized hermetic DSC pan. Samples were placed into a Q1000 differentialscanning calorimeter (TA Instruments, New Castle, Del.), equilibrated at55° C., and then ramped from 55° C. to 95° C. at 0.5° C./min. Using anempty pan as a reference, total enthalpy of denaturation (ΔH) and thetemperature corresponding to the nonreversible endothermic peak (T_(m))were recorded. Following the mDSC procedure, samples were vacuumdehydrated, and the fractional dry mass (ratio of dry weight to wetweight) was recorded.

[0342] 4. Data Analysis

[0343] The force and displacement data from the mechanical tests wereconverted to stress and strain. The stress and strain data for eachmechanical test were then fit to a high-order polynomial, and anequation for the specimen tangent modulus was calculated as thederivative of this polynomial. A plot of modulus vs. applied stress wasconstructed. The stress at the inflection point—the transition betweentension and compression—was the stress at which the second derivative ofthe polynomial was zero. The reference configuration was defined as thestress and strain at the pre-treatment inflection point. Threebiomechanical parameters were calculated from the modulus vs. appliedstress curves to quantify heat-induced changes in the mechanicalresponse (FIG. 19): the change in modulus at the inflection point (MI),the change in modulus at 150 kPa (M150), and the change in residualstress at inflection point (RSI). The percent change in hysteresis (HYST%) was calculated from the pre- and post-treatment load-displacementcurves. The change in the modulus at the inflection point is a measureof the increase or decrease in the stability of the joint, while thechange in the modulus at 150 kPa is an indication of how well the jointwill withstand physiologic loading. The percent change in strain at 0stress (E0%) was used to quantify axial shrinkage of the tissue.

[0344] Differences in each parameter with treatment temperature werecompared using a one-way analysis of variance (ANOVA). Post-hoc multiplepairwise comparison tests (Fisher's Least Significant Difference) wereperformed to determine differences between treatment groups with asignificance of p<0.05.

[0345] 5. Results.

[0346] a. Mechanical Testing

[0347]FIG. 21 includes various graphs representing observedbiomechanical parameters after varied heat treatments according to thepresent study as follows: graph (a) represents change in modulus at theinflection point (MI); graph (b) represents change in modulus at 150 kPa(M150), graph (c) represents percent change in strain at 0 stress (E0%),graph (d) represents change in residual stress at the inflection point(RSI), and graph (e) shows percent change in hysteresis (HYST %).Further to the graphs in FIG. 21, the reference letter “X” is used todesignate where data is significantly different from 37° C. group,p<0.05; whereas the symbol “+” is used to designate where data isobserved to be significantly different from the 85° C. group, p<0.05.

[0348] Significant differences between the control group and theheat-treated specimens were observed at temperatures of 70° C. and above(FIGS. 19, 20, 21). The variation increased with increasing treatmenttemperature. No significant changes were observed between the controlgroup and the 50 and 60° C. groups, and the 65° C. treatment groupshowed a change only in the hysteresis parameter. The modulus at theinflection point (MI) increased by 152 kPa after treatment at 70° C.(p<0.05), and continued to increase with increasing heat treatment: the85° C. group, with an average increase of 343 kPa after treatment asshown in FIG. 19), and was significantly different from both the controlgroup (p<0.001) and the 70° C. group (p<0.05) according to the graph inFIG. 21a. The modulus at 150 kPa (M150) significantly decreased forgroups treated at 70° C. and up, but did not continue to decrease withincreasing treatment temperature; the decrease was 17% at 70° C. and 18%at 85° C. as shown in the graphs of FIGS. 19, 21b.

[0349] Relative to the control group, significant axial shrinkage (E0%)was first observed at the 70° C. treatment temperature. There was nosignificant difference observed in this particular experiment betweenthe axial shrinkage after treatment at 70 and 85° C., although there wasa trend towards continued increase (p<0.10) according to the graphicalresults in FIG. 21c. The change in the residual stress at the inflectionpoint (RSI) after heat treatment was significantly larger for groupstreated at temperatures of 75° C. and up with a trend towards increasingstress with increasing treatment temperature (75 vs. 85° C., p=0.084),as shown in the graph of FIG. 21d. A 36% percent increase in hysteresis(HYST %) was observed for the 65° C. group; this was significantlylarger than that of the control group (p<0.05) per the FIG. 21e graph.

[0350] The disc heights of the specimen exposed to long heat treatmenttime at 85° C. stabilized after approximately 2.5 hours. As a result oftreatment, M150 decreased 47%, MI increased 625 kPa, RSI was 47.3 kPa,and hysteresis increased 98%. The percent change in strain at 0 stress(E0%) was 22.5%.

[0351] Heat treatment of the excised annulus at 85° C. resulted inshrinkage of 45.1%±5.5% in the circumferential direction and expansionof 56.9%±25.4% in the radial direction. The shrinkage was accompanied bya color change from white to translucent, a finding that which was notpresent in our whole-disc samples.

[0352] b. Microstructure

[0353] The structure of the annular collagen, as indicated by itsbirefringence under polarized light microscopy, varied with heattreatment (FIGS. 22a-f). The structure of the excised sample treated at85° C. changed dramatically relative to that of the control specimen:the 37° C. specimen was strongly birefringent under polarized light asshown in FIG. 22b, while the 85° C. excised specimen showed nobirefringence as shown in FIG. 22f. The 85° C. mechanical test specimenappeared less birefringent than the control, as shown in FIG. 22d.Bright light microscopy revealed a structure consistent with thatobserved under polarized light. The heated excised specimen exhibited ahomogenous morphology, as shown in FIG. 22e, with a complete loss of theoriginal structure relative to the control shown in FIG. 22a. Tissueorganization decreased, but was not absent, in the 85° C. mechanicaltest specimen shown in FIG. 22c.

[0354] c. Modulated Differential Scanning Calorimetry

[0355] The excised specimens did not exhibit an endothermic peak, andthus, values for T_(m) and ΔH were not calculable. Both intact groupsexhibited a full and clear endothermic denaturation event. There were nosignificant differences in T_(m) and ΔH between the intact (37° C. & 85°C.) specimens. T_(m) for the control group and the 85° C. intact groupwere 65.4±1.5° C. and 65.3±0.9° C. respectively, while ΔH was 11.5±2.4W/g and 12.2±4.6 W/g. The fractional dry mass of the 85° C. intact group(0.33±0.03) and the 85° C. excised group (0.37±0.043) were bothsignificantly higher than the control group (0.26±0.04; p<0.05 andp<0.01, respectively).

[0356] 6. Discussion

[0357] In this study we examined the acute biomechanical effects ofthermal treatment on the annulus fibrosus. The data demonstrate thattreatment for 15 minutes at 70° C. or above is required to producestatistically significant biomechanical modification of the intactmotion segment ex vivo. Heat treatments of 70° C. and higher resulted instiffening of the annulus at low loads (i.e. in the ‘toe’ region,parameter MI) and a decrease in stiffness at higher applied loads(M150).

[0358] These results suggest that thermal therapy at temperatures 70° C.and greater leads to a more stable transition from flexion to extension.The depressurization we performed during specimen preparation created aneutral zone at the transition between tension and compression, withinwhich small changes in force resulted in relatively large changes indisplacement. After treatment at higher temperatures, this neutral zonewas reduced or eliminated, as reflected in the graph shown in FIG. 20.It is further believed that the experimental model was illustrative of,and that this response would similarly affect, the neutral zone ofintact discs. By contrast, our observation that heat treatment attemperatures greater than 70° C. softens the annulus at higher forcessuggests that the acutely treated intact disc may be at increased riskof injury when brought to its range-of-motion limits. This confirms, inthe unique setting of vertebral discs, similar behavior that has beennoted in the shoulder capsule, where heat has been observed to bothacutely shrink and decrease the linear-region stiffness of the joint. Asa result of such prior observations in that setting, clinicalpractitioners have recommended joint protection for six to twelve weeksafter treatment.

[0359] While the trends in our data are comparable to those reported forother tissues such as the shoulder capsule, the magnitude of the annulartreatment effect in intact tissue is smaller. For instance, whileshoulder capsule contraction has been reported in at least one study tobe 60% after 80° C. treatment, we observed annular contraction of only7.8% (E0%) after heating the intact disc to 85° C. Similarly, shouldercapsule stiffness reductions at high loads were much greater than thoseobserved in the intact vertebral discs: we observed stiffness decreasesof 20% (M150), while shoulder capsule stiffness decreases were on theorder of 50%. It is believed that these differences are likely due toeither the unique joint structure or the fiber orientation of the intactannulus, or both. The shoulder data was derived from experiments inwhich the capsule, a linearly oriented collagenous tissue, was cut intostrips along the collagen fiber direction before testing. In contrast,intact annular collagen is oriented in two directions at ±65° to thespinal axis, and it is highly constrained both axially, by the adjacentvertebrae, and circumferentially, by its annular structure. When the insitu constraints on the annulus were removed by excising the tissuebefore heat treatment, we observed a 45% circumferential shrinkage,which is similar in magnitude to that reported for linear collagenoustissues. It is believed, therefore, based upon our observations, that insitu tissue constraint, rather than fiber orientation, may be thedominant mechanism responsible for the observed differences.

[0360] Our conclusion that in situ tissue constraint reduces the effectsof thermal therapy on the annulus fibrosus, though not previously knownor confirmed prior to this study, is further supported by resultsobserved in several other previously reported studies. In one previousreport, for example, only 6.6% shrinkage was observed in the patellartendon, a linearly oriented collagenous tissue, after in situ treatmentwith laser energy. This difference was attributed to constraints imposedby the intact joint. Similarly, a number of other studies have beenreported examining heat-induced changes in the mechanics of chordaetendineae. Tissue stress was observed to have a retarding effect: whentissue was stressed during heating, increases in the temperature, theheating time, or both, were required to achieve effects noted forunstressed tissue in these studies.

[0361] The mechanism by which tissue stress retards thermal denaturationhas a thermodynamic basis. Tensile stress straightens tissue collagenand decreases configurational entropy, which in turn, increases theactivation energy required for thermal denaturation. This retardingeffect was clearly evident in intact annulus, where we observed thatseveral hours of thermal treatment at 85° C. were required to achievemaximum contraction. In contrast, at least two groups of priorresearchers examining excised collagenous tissues achieved maximumcontraction within 5 minutes. Also, while M150 for an intact specimentreated at 85° C. for 15 minutes was only 18%, the decrease in stiffness(47%) after several hours of treatment at 85° C. was comparable to thatelsewhere reported for excised shoulder capsule tissue.

[0362] Our polarized light microscopy data provides further evidencethat tissue constraint effects both the temperature and time required toachieve a given amount of thermal damage. Collagen birefringencedisappeared completely after heat treatment for 15 minutes at 85° C. inthe unconstrained specimen, but it remained in the intact treatedannulus. Clearly 15 minutes of treatment was not sufficient to fullydenature the intact annular tissue. While it was not possible toquantify the degree of birefringence in the intact tissue aftertreatment at 85° C. relative to that at 37° C. with only one specimen,it appears that that the treated specimen was less birefringent than thecontrol. These observations are consistent with the results of ourmechanical tests.

[0363] Differences in the mechanical behavior of the intact annulusafter treatment at temperatures greater than 70° C. indicate that thetissue underwent a thermally mediated change. However the results of themDSC experiments indicate that tissue constraint prevented significantcollagen denaturation: the main denaturation peak and enthalpy ofdenaturation of the intact annulus were unaffected by 15 minutes oftreatment at 85° C. Although the increase in hysteresis after treatmentimplies an energetic change, the mechanisms by which the tissue wasthermally modified are unclear. One possible explanation is provided bystudies examining both the structure of collagenous tissue usingscanning electron microscopy (SEM), and endothermic events, using DSC.Using these techniques, several investigators identified discrete stagesof the denaturation process. They attributed the earliest denaturation(<56° C.) to the destruction of heat-labile cross-links (which are morepronounced in young animals), and showed that the structure of thefibrils remain intact during this process.

[0364] A second contributing factor for the biomechanical changes issuggested by the observed increase in fractional dry mass in both ourconstrained and unconstrained treated tissue relative to the controltissue. The increase in fractional dry mass indicates that the tissuesheated at 85° C. swell less when equilibrated in saline. Since annulartissue hydration has been disclosed to be related to proteoglycancontent, our finding indicates that the proteoglycans of the annulushave been affected by the heat treatment. Similar to collagen,proteoglycans are susceptible to denaturation through destruction ofheat-labile hydrogen bonds. Alteration of annular proteoglycan canaffect tissue properties since they have been previously disclosed toplay a role in stabilizing the collagen matrix, as had been observedaccording to at least one prior disclosure in articular cartilage wherethe modulus decreases significantly when the proteoglycans are removed.It is thus believed that a portion of the observed biomechanical changesis due to changes in proteoglycan, the thermal properties of which arenot extensively understood according to prior publications. Confirmationof such belief as to the specific mechanism with respect toproteoglycans may be achieved according to further study and observationby one of ordinary skill based upon review of this disclosure.

[0365] The retarding effect of stress on annular denaturation has anumber of clinically relevant implications. First, to achieve asignificant degree of collagen denaturation in vivo, the annulus shouldbe heated either for long times or at high temperatures, or both.Second, thermal treatment according to the devices and methods of thepresent invention may be applied in a selective fashion. Sinceunstressed annular fibers are more susceptible to thermal treatment thanstressed fibers, areas of slack tissue (e.g. the inner annulus indegenerating discs) are preferentially heated, while preservingstructurally competent areas that are carrying stress (e.g. the outerannulus that retains stress into later stages of degeneration). Further,patient pre-positioning is desired for certain circumstances, allowingthe practitioner to selectively stress particular annular regions,thereby further controlling the zone of biomechanical alterations.

[0366] In another regard, the present invention provides a useful toolwhen applied to selectively shrink proliferative fibrocartilageresponsible for annular protrusion and prolapse. This is accomplishedfor example by providing the thermal therapy to degrade proteoglycansand decrease swelling.

[0367] In still a further regard, and as further supported by theresults of this study, the present invention is used to provide thermaltherapy in a manner specifically adapted to ablate annular nociceptorsand cytokine producing cells while sparing tissue material properties.Thermal therapy in the range of 48-60° C. is sufficiently low to avoidcollagen denaturation and biomechanical changes, yet this temperatureregion is desired for modes of thermal spine treatment intended toinduce nerve injury and cellular death without significant biomechanicalchange from the heating (or with biomechanical change if desired andbrought about by other means).

[0368] It is to be further appreciated that the results of this study,as to specific ranges and/or numbers, are potentially limited by the useof non-degenerate porcine intervertebral discs. While porcine discs aresimilar to human discs in many ways, there may be differences indenaturation temperature, which is dependent on a number of factors suchas collagen cross-link type and density. However, the consistent tissuequality and size afforded by the porcine model minimizes inter-specimenvariability and therefore provides a good system by which to investigatemechanisms of thermal/biomechanical interactions. The disc height alsodiffers between human and porcine lumbar discs. Since the lumbar humandisc is generally taller (averaging approximately 11 mm) than theporcine disc (averaging 3 mm in this study), it may be less influencedby vertebral constraint and therefore more able to thermally contract.In this regard, as with many previously disclosed devices and treatmentmethods, the exact extent of effect may vary even between speciesaccording to varied anatomy.

[0369] Notwithstanding the foregoing, future studies may be performed onhuman discs according to one of ordinary skill based upon thisdisclosure to confirm effects of specific treatment regimens. Moreover,it is further believed that the relationship between varied temperatures(and/or ranges) and predictably varied results are well correlatedacross species, though specific temperatures, temperature-time dosing,or magnitudes of observed results may differ. Accordingly, it isbelieved that the studies disclosed herein and aspects of the inventionrelated thereto provide beneficial treatment regimens, though such mayclearly require further tuning in order to be particularly adapted forspecified use in treating a particular patient, patient group, or evenanimal type.

[0370] Further to the experimental model of the present Example, nucleardepressurization allowed for the biomechanical response of the intactannulus to be isolated. However, for intact discs, nuclear pressure willincrease annular stress and therefore is believed to further retardthermal effects beyond that observed here. Finally, the ex vivo studysummarized herein does not characterize any subsequent biologicremodeling that would occur after heat treatment in vivo. Remodelinglikely further modifies annular tissue properties, and the magnitude andtemporal sequence of this response may be further characterized in asuitable in vivo model. However, the acute effects provided hereunderprovide significant benefit notwithstanding such potential forremodeling.

[0371] Despite these limitations, the foregoing observations and relateddescription demonstrates a number of mechanisms by which thermal therapyinfluences the biomechanical response of the annulus fibrosus. Uniquefeatures of the disc—specifically tissue structure and stress-strainconstraints due to attachment to adjacent vertebrae—have significantimpact on the thermal treatment effect size. Future in vivo animalstudies and controlled human trials may be further performed by one ofordinary skill in the art based at least in part on this disclosure inorder to further link biomechanical and biological consequences oftissue heating to the various beneficial patient outcomes.

External Directional Ultrasound Thermal Treatment (“ExDUSTT”) System andMethod

[0372] The following description relates generally to FIGS. 23-53 andprovide further illustrative embodiments of the invention according tomodes previously described above for providing an external directionalultrasound thermal treatment (or “ExDUSTT”) device, and method fortreating spinal disorders therewith.

[0373] As illustrated in FIG. 23, the illustrative ExDUSTT applicator110 of the present invention preferably has a support member 120 with anultrasound transducer 130 mounted thereon within an outer covering 150that is typically an inflatable coupling balloon such as is shown.

[0374] According to the further view shown in FIG. 24 during one mode ofuse in treating a region 108 of an intervertebral disc 104 associatedwith a spinal joint 101, the transducer is generally chosen to be acurvilinear panel that is both directional and focusing (e.g. convergingsignals) to help highly localized deep heating, in particular useful forapplications from outside the disc as shown. It is to be appreciatedthat “spinal joint” where used throughout this disclosure generallyincludes intervertebral discs, adjacent vertebral bodies, and associatedstructures such as posterior vertebral elements such as facet joints.

[0375] As shown in FIGS. 25 and 26, respectively, ExDUSTT devices of thepresent invention can be on many different delivery platforms, such as arigid pre-shaped platform shown in FIG. 25 with the transducer 130 onthe distal bend section 116 and canted at an angle A for angulardirectional ultrasound relative to the proximal shaft 112 axis, or on acatheter-based platform shown in FIG. 26. Both chassis are beneficialfor respective purposes, and each for common purposes. However, thepre-shaped probe is in particular useful for angular directional heatingat hard to reach places in the body, such as certain spinal locations,and the rigidity helps position control.

[0376]FIG. 27A shows an illustrative rigid probe device 200 in finerdetail for further understanding. Distal shaft 202 includes a 4 mm outerdiameter brass tube 204 with 0.008″ silver lead wires 206 and water flowlines (e.g. 0.0226″ polyimide tubing) contained therein and coupled atthe proximal end portion (not shown) to a proximal adapter. A distal0.1135″ stainless steel tubing 208 is shown secured with epoxy 210within the brass tube 204, and has a window 212 cut out leaving supportridges upon which the transducer 230 is mounted with Nusil 1137Silicone, as shown in finer detail in FIG. 27B. Further included beneaththe transducer 230 are rubber threads 236 strung across the window 212to help provide a good non-dampening support system. An outer inflationballoon is shown at 240 and in shadow in the expanded condition fortissue coupling. As can be appreciated from the figure, an air backingis thus provided at 238 to provide highly directional ultrasounddelivery away from the central shaft of the device and out through theeccentric inflation balloon 240 and into tissue there. Moreover, asillustrated in FIG. 27B, the transducer 230 is curvilinear around anaxis that is aligned with the long axis of the support shaft and thus isfocused into tissue along the transducer and balloon length as such. Forthe purpose of a complete description, one exemplary transducer that hasbeen observed to be useful in this and other ExDUSTT designs hereinshown and described has for example the following specifications: 0.394″long×0.98″ wide×0.013″ thick PZT4, 0.59″ radius of curvature.

[0377] Various modifications may be made to the device just shown anddescribed. For example, the balloon according to that Figure waselastomeric type, such as 0.005″ wall silicone balloon. However, betterrepeatability of size and shape may be required than what suchelastomers can offer, and thus a less compliant balloon of the preformedtype may be used. This is shown for example at balloon 248 in FIGS.28A-B that is for example a pre-shaped PET balloon having a wallthickness for example of 0.001″. Further considerations for materialsmay be considered, such as for example thermal properties, ultrasoundtransmissivity, profile, etc.

[0378] Moreover, similar features as just described for the ExDUSTTdevice may be incorporated onto a different catheter chassis withoutmuch required modification, as referenced in FIGS. 29A-B. Here aproximal catheter shaft 250 is shown coupled to a distal 4 mm OD brasstube 254. Everything else may be the same as described above for therigid probe designs. The catheter shaft 250 may be multi lumen, or maybe a bundle of lumens, etc.

[0379] The transducers shown in the previous FIGS. are not the onlyconfigurations contemplated, either. For example, FIGS. 30A-B show acurvilinear transducer 260 with its radius of curvature R around an axisthat is transverse (e.g. orthogonal) to the long axis L of the supportshaft 280.

[0380] Further understanding of various modes of operating devices ofthe rigid probe type just shown and described are provided in FIGS.31A-32B, which reflect operation at 5.6 MHz optimal frequency, with peakefficiency at 40%, and linear output and efficiency out to 12W appliedwith 5.5 W emitted from the transducer.

[0381]FIG. 33 shows a test set-up for ex-vivo pig spine treatment usinga catheter-based ExDUSTT device over 5 minute heating period, and showscertain measured temperatures during a relatively low temperature modeof operation. T1 is a temperature probe 5 mm deep into tissue from thetransducer coupling interface, whereas T2 temperature probe shows thetemperature profile over varied depths from the transducer.

[0382] In contrast to the ex-vivo data shown in FIG. 33, FIGS. 34A-Bshow results for in-vivo treatments in pig discs, and show temperaturesall exceeding 55 degrees, though temperatures close to the transducerexceeded well over 65 degrees and even up to 80 degrees.

[0383] As illustrated in FIG. 35, various different sizes may be useddepending upon the particular need, and a kit of different sizes,lengths, angles, etc. may be provided. The devices 270, 280 shown inFIG. 35 generally differ in that the larger device supports a 3.5 mmwide ultrasound transducer, whereas the smaller device supports a 2.5 mmwide transducer. In general, other features may be similar unlessdesired to change them, whereas for the embodiment kit shown, eachdevice has other components scaled to meet the 2.5:3.5 comparison forthe transducer widths. Other variations may be made, however.

[0384] For the purpose of further characterization, and understanding ofdirectivity and focus of energy delivery as relates to the presentinvention, FIGS. 36A-B and 37A-B show certain output power profilesacross the transducer faces for both 2.5 mm and 3.5 mm curvilineartransducers, respectively. The radius of curvature for these transducersis around an axis that is aligned with the long axis of these plots.

[0385] Various thermal treatment studies have been performed withworking prototypes of the present invention and will be explainedhereafter in part by reference to the test set-up for the rigid,pre-shaped bent ExDUSTT device shown in FIG. 38.

[0386] For example, as shown in FIG. 41, all temperatures monitoredusing 0 degree C. cooling during relatively high temperature mode ofoperation were above 60 degrees C., even out to 10 mm deep, and inparticular were above 70 degrees C. for most all data taken at 5 mmdepth, whereas temperatures predicted at 7 mm deep were also in excessof 70 degrees. Other illustrative and informative results are reportedup through FIG. 53 with respect to additional modes of ExDUSTToperation, which are best understood by further reference to the BriefDescription of the Drawings above.

[0387] Various different modes and embodiments for curvilineartransducers may be suitable for use according to the various embodimentsherein described, such as for example the various ExDUSTT deviceembodiments just described However, the following provides some furtherdetail for particular modes and variations contemplated for the purposeof providing a more complete understanding

[0388] In one regard, these transducer segments such as used in theExDUSTT devices (and per for example the earlier embodiment in FIG. 6C)are sectors of larger diameter cylinders or plated tubes, withultrasound energy emitted from the concave surface. Examples include0.394″ (±0.005″)×0.098″ (±0.002″) linear wide×0.013 thick which form an14.2 deg. Arc segment of 0.4 ″ inner radius tube. One can realizedifferent diameters or arc segments, such as 9.5 deg. Arc segment of0.591″ inner radius tube. These can be purchased for example fromvendors such as Boston Piezo-optics using materials such as PZT-4, 5, or8.

[0389] The radius of curvature can be selected to sharpen or decreasethe amount of energy concentration or apparent focusing (i.e., radius ofcurvature of 0.5, 0.75, 1.0, 1.5, 2.0 cm can be appreciated) with thehigher radius of curvature and wider transducers giving more penetratingdistributions. The width can vary to suit particular needs for operationor device compatibility, but may be for example between about 1.5 mm toabout 6 mm; whereas the length can also vary to meet particular needs,such as for example from between about 2 mm to about 10 mm or greater.Transducers meeting these specifications are in particular useful forvarious of the embodiments herein described, provided however that suchembodiments nor other aspects of the invention should not be consideredto be so limited to only these dimensions.

[0390] These transducers can be mounted in transducer assemblies using avariety of suitable means. Flexible adhesives (e.g. silicone adhesive,Nusil), rigid epoxies or conformal coatings (Dow Corning) may be used.Rigid metal (brass or stainless steel) or plastic assemblies can bemachined to hold the transducers and maintain air-backing. One moredetailed example incorporated into many of the ExDUSTT devices shown anddescribed includes a filed down, 15 mm long portion (or specifiedlength) across a 180 degree plane transversely through a distalstainless-steel support hypotube. This forms a shelf for either side ofthe transducers to be mounted. Lead wires (such as for example eithersilver lead wire or miniature coaxial cable (Temflex, Inc)) are solderedto the transducer surfaces for power application and can be run withinthe central lumen of the SS.

[0391] A thin layer of silicone adhesive can be placed upon the edges ofthe tube structure, and the transducer segment placed. The transducercan then be sealed using silicone adhesive and/or conformal coating. Theconformal coating can be accelerated using elevated heat for about 60min. Alternatively, rubber thread can be used for a spacer with siliconeadhesive, to keep transducers from contacting the metal surface. Otherholding devices can be implemented, including pieces machined from brassbar or rod with gaps for the air space and offsets to support. In someimplementations, it may be desired to circulate water or fluid behindthe surface of the transducers.

[0392] These transducer assemblies can be either modular catheter forminsertion into target tissue (intra-discal) or rigid externalapplicator. It is not necessary, but these transducers can be sealedusing epoxy and polyester layers a previously described, or usingmineral oil or other type of oil instead of Epotek, or the transducercan be left bare, though in many applications would be sealed on itsedges and possibly top surface with conformal coating for watertightintegrity and durability. Custom multilumen extrusions in materials suchas pebax can form the flexible catheter member of which the transducerassembly is attached. The transducers are rigid, but if multiplesegments are used, they may be coupled in a manner providing flexiblehinges for better bendability in use.

[0393] Pre-shaped high-pressure balloons such as those herein shown forultrasound tissue coupling can be provided in various shapes. Suitablesources include for example custom fabrication, such as for example byAdvanced Polymers, or may be made in house by heat-stabilizing the PETheat-shrink in pre-determined shape using molds and Teflon-coatedmandrels. These balloons can have a neck that is 3 mm OD and a one sidedinflation with a 2 mm radius. Compliant balloons using silicone, c-flex,polyurethane, or other material can also be used for variousapplications indicating such compliance or elastomeric properties.

[0394] These devices can have temperature regulated flow, flow ingeneral, or no flow at all. In addition, devices without encapsulatingballoons can be realized with sterile saline or fluid flow used to cooland couple US to the interface.

Internal Directed Ultrasound Thermal Therapy (“InDUSTT™”) System andMethod

[0395] The following description relates to device and methodembodiments in particular adapted for use internally withinintervertebral discs or other joints, e.g. “InDUSTT” devices andmethods.

[0396] The following figures and accompanying description is to be readin conjunction with prior description herein made above, and in anyevent relate to InDUSTT devices such as that shown at catheter 290 inFIG. 54. More specifically, FIG. 54 illustrates arrangements for twoalternative modes of InDUSTT assemblies and treatments as follows.Catheter 290 is shown at the top of the Figure in a “direct couplingmode” and is adapted to be delivered directly into a region of a spinaljoint, e.g. within the disc or bony structure, with the transducercoupled directly to tissue. Thus, there is only shown a coupling 294such as for electrical leads 296, and fluid cooling coupling 298. Asshown in the assembly of FIG. 54 on the bottom, however, a cathetercooled or “cc” arrangement differs from the direction coupling or “cc”arrangement in that a catheter 290 is buried within a closed housing ofan outer delivery device 300 that has a sharp pointed tip 302 forpuncturing into an intervertebral disc. Water circulation ports 298,310according to this arrangement cycle cooling fluids between a lumenwithin the internal catheter 290 and over the internal catheter 290 butwithin the outer sheath 300.

[0397] Further details of the cc arrangement are variously shown inFIGS. 55A-C, wherein a transducer 320 is of a cylindrical tubular typethat has sectored grooves 322 (FIG. 55C) on either side of an electrodedand active portion 326 for directional ultrasound delivery along about a90 degree span of space radially outward from that section, and thusboth directionality is achieved, as well as diverging US signal.

[0398] Couplers shown include power lead coupler 294, water inflowcoupler 298, water outflow coupler 310. As shown in FIG. 55B, the watercooling is aided by a distal port 299 in the internal catheter device290. A thermocouple 330 is shown along the active sector, as well asothers may be provided elsewhere (not shown) such as along the otherdead sector as temperature monitoring may still be important there toprotect certain tissues from conductive heating during US therapy on theopposite side of the catheter. The transducer shown may be for example1.5 mm outer diameter, 0.9 mm inner diameter, by 10 mm long and mountedover a plastic support ring. The outer catheter 300 may be for exampleconstructed from a simple polymeric tubing such as made from CELCON™from Best Industries typically used conventionally for implantingradiation seeds in tumor therapy and of 13 gauge construction.

[0399] For the purpose of providing a thorough understanding of the manydifferent aspects and considerations of using the InDUSTT device justdescribed, a significant amount of summary results from multiple studiesof working embodiments is herein provided by reference to FIG. 56A andbeyond. A thorough understanding of various aspects of these results andexperimental arrangements shown is gleaned by review of the BriefDescription of the Drawings above. In general, where discs are indicatedby an arrangement such as “C3-4” or “C4/5” such designates the vertebraein the animal between which the disc was treated. In addition, curvelegends designating numbers for graphs (such as for example “Probe 1-1”,“Probe 1-2”, etc. in FIG. 65A) designate thermocouples along temperaturemonitoring probes in the disc tissue, typically spaced by 5 mm apart.

[0400] Accordingly, as is reflected in the graphs and other pictures andFigures, many different discs were treated. Still further, the testresults shown also reflect an understanding of the effects of cooling atdifferent temperatures, as well as direct coupling versus cathetercooled coupling, as well as relatively high versus relatively lowtemperature modes of use.

[0401] While the results shown in these latter FIGS are in non-humananimal models, the results, and in particular the relationships betweenresults between different treatment groups, correlate to the humancondition and are confirmed by earlier human cadaver studies performed.Actual values may of course differ, however, but it is believed that theextreme ends of the results would apply across vertebrate animalspecies. Moreover, the date suggests that directivity is confirmed, asis the ability to achieve high temperatures over 70 degrees or even 75degrees, as well as control heating to lower temperatures for otherintended treatments.

[0402] In one example, FIGS. 59A and B show two sets of lines that crossat time equal to about 9.00 seconds. This indicates a period of timewhen the InDUSTT device, with sectored, directional ultrasound emission,was rotated. Accordingly, the uniform change in temperature reflects thepreferential heating that can be achieved with such device and notheretofore possible. For further illustration, FIG. 65A shows similarresults according also to turning a directional device to realign theactive sector to different transducers.

[0403] Various embodiments have been herein described, includingExDUSTT, InDUSTT, rigid-probe based, catheter based, directly coupled,actively cooled, sectored transducers, curvilinear transducers, axiallyaligned transducers, transversely aligned transducers, relatively largetransducers, relatively small transducers, compliant elastomericcoupling balloons, relatively non-compliant pre-formed couplingballoons, relatively high temperature modes of operation, relatively lowtemperature modes of operation, low temperature cooling, roomtemperature cooling, preshaped, flexible, guidewire delivery, anddeflectable/steerable delivery platforms. It is to be appreciated thatthe more detailed description for such embodiments provided herein isfor the purpose of illustration, and other modes of achieving such maybe suitable for inclusion according to the invention without departingfrom the present scope. Moreover, the combinations of such featuresherein shown are highly beneficial, but not intended to be limiting.Other combinations may be made without departing from the intended scopehereof. For example, the particular embodiments shown and described for“ExDUSTT” applications are described as such merely according to theirhighly beneficial ability to perform in that arrangement, but they maybe used as InDUSTT devices as well, despite their particular externaluse benefits. The opposite is true, as well, with respect to InDUSTTdevices which may also be used in other external locations such as fordisc heating. The devices shown and described may be used within oraround the bony structures of spinal joints, too. Moreover, wherevarious of the features may be highly beneficial for particularapplications, they may not be necessary for other applications. Forexample, directional energy delivery is a highly beneficial aspect ofthe various ultrasound embodiments herein shown and described, inparticular where highly localized heating is desired while othersurrounding tissues need to be protected such as nerves. However, inother applications, such as some complete disc remodeling applicationsfor example, non-directional emission may be suitable to heat all thesurrounding tissue equally.

[0404] It is to be appreciated that the various modes of devices andoperation herein described, together with tissue characterizationstudies performed and herein presented, provide a significantunderstanding with respect to adapting and controlling thermal therapy,or other modes of ultrasound delivery for therapy, in special areas inthe body such as joints, and in particular spinal joints and their discsand bony structures. Back pain and other issues in these joints aresignificant medical issues that may be addressed with the presentinvention according to its many different modes and aspects.

Long-Term Implantable Ultrasound Delivery Devices, Systems, and Methods

[0405] The foregoing embodiments, including the devices, systems, andmethods described, have been generally described above with respect totheir use as temporary implants, (e.g. per the percutaneous catheter orprobe devices and respective treatment techniques described in thepreceding Figures, such as for example with respect to the variousExDUSTT and InDUSTT devices shown and described). However, according toa highly beneficial aspect of the present invention, an ultrasoundtreatment system and method is provided for long-term implantation,either permanent or semi-permanent, as is described in more detail belowby reference to various embodiments.

[0406] The long-term implantable ultrasound system of the invention isshown schematically according to various illustrative embodiments inFIGS. 66-68 by reference to a patient's body 402 that includes a spine404 and outer skin barrier 408.

[0407] More specifically, FIG. 66 shows long-term implantable ultrasoundtherapy system 400 and includes a long-term implantable ultrasoundtreatment assembly 420 positioned at a location adjacent to a spinaljoint 406. A coupling assembly 430 connects treatment assembly 420 witha control unit 440 that is shown in this embodiment to also be implantedas a long-term implant within the body 402 of the patient. Control unit440 includes for example a power source 442 that cooperates with acontroller 444. Further to the illustrative embodiment, control unit 440is adapted to communicate with an external assembly 460 via atransmitter 448 and a receiver 450 of control unit 440 and reciprocaltransmitter 468 and receiver 470 for external assembly 460. Suchcooperation may be for example in order to provide telemetry to receiveand process data monitored by control unit 440 regarding the treatmentwith ultrasound assembly 420, such as monitored parameters including forexample temperature, thermal dose, number of treatments, duration oftreatment, power levels. Or, such cooperation between internallyimplanted control unit 440 and external assembly 460 may be for thepurpose of downloading new software such as operation protocols to thedrive unit tailored to advance therapy to account for new therapeuticinformation or to advance or otherwise modify an overall therapyprotocol to a different stage. Or, to the extent power source 442 is arechargeable battery, coupling between control unit 440 and externalsource 460 may be done for the purpose of recharging the battery, whichmay be done across the patient's skin barrier 408 according topreviously disclosed methods, though which may be modified to meet theparticular needs for a particular case. Examples of such remote,transdermal power recharging include use of induction by creating amagnetic field across the skin barrier 408 in a particular manner so asto recharge the batter of power source 442.

[0408]FIG. 67 shows another embodiment similar to that of FIG. 66,except however that control unit 440 is positioned externally of body402 such that coupling assembly 430 bridges across the skin barrier 408.This provides the ability to recharge, monitor, control the control unit440 and related treatment without requiring the remote transmissionacross the skin barrier 408 and other tissues as required in the FIG. 66embodiment. According to this and the FIG. 68 embodiment, the externallylocated control unit 440 has a coupler 446 that is adapted to couple toexternal assembly 460 via its reciprocal coupler 466, which is shownschematically but may be for example for similar communication purposesprovided above with respect to sending and receiving data and otherinformation to monitor or control therapy.

[0409] In addition, such couplers 446,466 may provide for a rechargingof the power source 442, such as a rechargeable battery. In stillanother regard, control unit 440 may be replaced by a simple coupler forthe various leads connecting ultrasound assembly 420 with the outsideworld, and all control of therapy is done via a removable attachment tothe external assembly 460. This may in particular be useful with respectto therapy protocols requiring relatively few, discrete applications ofenergy that will thus allow for selective attachment to the therapeuticcontrol system.

[0410]FIG. 68 shows yet another embodiment similar to FIG. 67, excepthowever illustrating that the ultrasound treatment assembly 420 ispositioned within a structure of the spinal joint 420, which may be forexample a bony structure such as vertebral body or posterior body, e.g.facet joint, or may be an intervertebral disc.

[0411] It is to be further appreciated that these embodiments, and inparticular the embodiments of FIGS. 67 and 68 providing external accessto control unit 440, may benefically provide features not easilyprovided in the completely implanted embodiment of FIG. 66. For example,cooling assemblies may be incorporated into the externally accessibleembodiments, such as circulating cooling fluids to a cannula portprovided there. However, it is further contemplated that cooling may beaccomplished with the fully implanted assembly, such as by circulatingcooling Freon within a closed internal loop between control unit 440 andtransducer assembly 420, or merely circulating water at body temperaturetherebetween, though such may be gradually elevated during the thermaltherapy, but nevertheless provides a heat sink to circulate heatconduction away from the treatment area.

[0412] Accordingly, the various embodiments previously described abovewith respect to ExDUSTT and InDUSTT ultrasound delivery systemarrangements may be appropriately adapted for use with the long-termimplant arrangement of the present invention to provide long-termthermal therapy with various beneficial aspects of those prior devices.Such modifications may be made, for example, to materials ofcontruction, shapes, size, etc., to adapt them for particular intendedlong-term use. Moreover, various disclosures cited above with respect tolong-term electrical implants may be further modified to accommodate theparticular needs to delivery, drive, operate, and monitor ultrasoundtherapy according to the present invention. In addition, variousfeatures provided with respect to other ultrasound energy deliverysystems disclosed among various published references may also beappropriately modified with respect to the long-term, implantableultrasound therapy provided herein.

[0413] It is to be appreciated therefore that the present inventionsatisfies the foregoing needs left heretofore unmet by prior disclosuresby implanting, in one regard, an ultrasound therapy source in thepatient and providing for the heat source to be controlled automaticallyor manually. This allows for automatic, periodic treatment and/or manualcontrol by a patient or health care professional.

[0414] By way of example, and not of limitation, in addition to thevarious embodiments provided herein above by reference to the variousFigures, a heat source such as that described in U.S. Pat. No. 5,620,497(but miniaturized if desired) would be implanted in a target site. Thetarget site could be soft tissue, a joint, the spine, or any otherlocation in the body where application of heat will yield a desiredeffect. Coupled to the heat source is a control apparatus, such as amicroprocessor, that will activate the heat source at predeterminedtimes to automatically provide for periodic treatment. Usingconventional programming techniques, the microprocessor can administer atreatment continuously or at spaced apart intervals. Application of heatduring a particular treatment interval can be with continuous wave heator pulsed application of heat. Combinations of continuous wave andpulsed application of heat can be programmed as well. The treatmentcould be repeated after a predetermined time period, such as once everyhour, once every day, or any other desired period of time. Anotherexample of a treatment would be to heat a target region for a fixedduration once every week for two months. Such controls would becontained for example in the control module 440, or external assembly460, or a combination of resources allocated between them, such as shownfor example in any of FIGS. 66-68.

[0415] It is to be further appreciated by reference to the illustrativeembodiments of FIGS. 66-68 that control of the applicator should beconsidered broadly, though particular benefits are gained by each of theparticular embodiments between those figures such that the applicator(heat source) can be activated/controlled via telemetry, an isolatedself-contained implantable control unit, or via percutaneous orextracorporeal connection (such as catheter(s)) to exterior control andmonitoring device(s).

[0416] In one further mode, a manual control can be provided so that thepatient can “force” a treatment in response to pain or another sensorystimulus. The software will “intercept” the manual control signal andcompare the time between the manual control signal and the priorautomatic treatment, or between two prior manually forced treatments, todetermine if the interval between treatments is too short. If so, themanual control would be locked out until at least a predeterminedinterval has passed. Optionally, the passing of the interval can besignaled to the patient using visual and/or audible indicators such aslights and buzzers. Or, more control can be left to the patient withoutsuch preventative measures required.

[0417] The control apparatus portion of the invention can be external tothe patient, such as worn in pouch on a belt or in any other convenientmanner. Such applies for example to either or both of external assembly460 (if included) and control unit 440 (e.g. per the FIGS. 67-68embodiments). Leads from the ultrasound transmission source would, inthat case, extend through the patient as is known with otherelectrically operated implantable devices such as for example certaininsulin pumps or temporary cardiac pacemakers or defibrillators. Thepatient then could wear the apparatus, and an associated battery powersupply, on his or her body.

[0418] In another embodiment, the entire apparatus, including powersupply, could be implanted, again using techniques and arrangementsknown for other systems and methods, such as in the cardiac pacemakerart, electrical spinal stimulator systems, and the like. Another exampleincludes an implantable ultrasound heating apparatus adjacent tointervertebral disc for chronic treatment of lower back pain. The devicecould deliver a single treatment session on demand (pain) of thepatient, or follow some protocol.

[0419] According to further embodiments, temperature sensors could beused for treatment control and verification-feedback. A heating oracoustic device can be inserted into a tumor for repeated heating andactivation of chemotherapeutic agents on a semi-regular basis. A drugcan be released from the applicator, such as via a reservoir or elutingcoating, or another implant closely associated therewith.

[0420] It is further contemplated that the devices of the presentinvention beneficially use ultrasound delivery according to highlybeneficial embodiments. Such delivery may be for heating, such asdescribed in detail above by reference to the prior embodiments. Or,such ultrasound delivery may be for other purposes in addition to oralternative to heating, as will be explained further below. Moreover,other sources may be used in conjunction with or instead of ultrasound.Radio-frequency current, microwave, thermal conduction based sources,magnetic, and laser sources can each be utilized.

[0421] Additional examples of various modes of use include, but are notlimited to: frequent ultrasound exposure to bony endplates to stimulatebone growth; intervertebral fusion; and ultrasound exposure ofpostero-lateral processes for fusion.

[0422] Accordingly, the invention provides a long-term, permanent orsemi-permanent implant, and thus modifies the non-permanent devicesheretofore used for ultrasound thermal therapy. The heat source wouldemploy biocompatible, flexible technology that can be permanently orsemi-permanently implanted to maintain the desired treatment (whetheracoustic exposure or thermal) protocol. Moreover, it is alsocontemplated that, despite the benefits provided for such long-termadaptive use, the present embodiments may also be used as temporaryimplants, such as in certain more acute settings under the care ofhealthcare professionals.

[0423] The wire leads for thermometry sensing and power leads areconnected through skin/body wall and sutured in place. Cooling tubes maybe further provided if cooling is necessary or desired. For example,such cooling arrangements as described above for the previousembodiments may be further adapted for use in the long-term implantsystems of the present embodiments, including with respect to particulartemperatures, such as for example at: less than 37 degrees C. (such as 0degrees C.); over 37 degrees C.; and in some cases 43 degrees C. orabove. Moreover, the various modes for fluid flow in and around thetransducer may be used, and cooling may be provided for tissue interfaceregions, or for non-targeted tissues.

[0424] Further contemplated for use within system 400 according to thevaried embodiments among FIGS. 66-68 may be temperature regulation, suchas by use of thermal sensors (e.g. thermocouples or thermisters) locatedin or around the transducer assembly. Such aspects may be according tothe various embodiments incorporating temperature monitoring and controlas elsewhere herein described for the various embodiments above.

[0425] Tissue coupling may also be achieved according the variousembodiments elsewhere herein described for temporary implants, thoughmay be again modified to suit the particular needs for long-termimplantation, such as with respect to minimizing the intrusiveness byproviding reduced dimensions (e.g. with respect to coupling pads orballoons), or modifying the types of materials used. For example, forhighly compliant balloon materials, long term inflation may result insignificant creep and expansion of the membrane that may produceundesired results, and thus for certain such long-term implants balloonsof the less compliant construction may be desired with respect to thatconsideration. However, the balloon materials may also be chosen tominimize potential long-term wear and tissue erosion issues that mightarise at the tissue interface. This may be particularly important forimplants at locations where motion is experienced, such as at mobileportions of spinal joints. In such case, more compliant balloonmaterials may be less traumatic over prolonged periods of time withmovement experienced at such interface.

[0426] It is contemplated that the overall cooperation betweencomponents in system 400 shown in FIGS. 66-68 may be accomplishedaccording to a wide variety of arrangements, and thus the couplingassembly 430 is shown very schematically. Such assembly 430 may includefor example a single cannula connecting transducer assembly 420 andcontrol unit 440, which cannula may house transducer power deliveryleads, fluid delivery lumens for coupling balloon inflation and/orcooling fluid circulation, temperature sensor leads, or the like. Thesemay share lumens in various combinations, or a multi-lumen assembly maybe provided. Or, separate members may be used to connect such couplingelements between control unit 440 and ultrasound transducer 420. In thisarrangement, though more attaching members are strung within the body,they may be rendered smaller and more flexible, and their overall effectmay be less intrusive to the body's internal environment than wouldresult from a single or even multiple combination bundle(s),respectively.

[0427] The various modes of operation for the ultrasound implantsgenerally require use of an RF Oscillator, such as for example operatingbetween about 0.5 to about 12 MHz, and with pulse modulation for variousof the modes described above, or without such modulation for continuouswave embodiments. Moreover, an RF power amplifier may be incorporatedtherewith. Such may be provided in the control unit 440 directly coupledto the ultrasound transducer 420 and worn as the internal or externalimplant in or on the patients body, respectively, per the embodimentsshown in FIGS. 66-68. Or, coupling to a remote external source withthese features may be used, such as at external assembly 460 in thoseFigures. This may be in particular the case for example when therapeuticultrasound delivery is desired only at discrete periods of time and thepatient may hook-up to the RF drive assembly that drives the transducer.

[0428] Accordingly, RF sources previously described with respect toultrasound therapy systems, or those previously disclosed for use withrespect to electrical energy delivery implants, may be modifiedappropriately to meet the unique needs for driving the long-termimplantable ultrasound transducers of the invention and according to thetherapeutic ranges desired, such as those illustrative modes ofoperation herein described above.

[0429] Various modes of ultrasound delivery are contemplated, either toprovide thermal therapy, or non-thermal ultrasound therapy, and whetherto provide for mechanical tissue remodeling, controlled cell death, orenhanced tissue permeability to drug delivery. In one regard, withrespect to desired levels of thermal therapy using the ultrasoundsystems, such modes of therapy previously described above with respectto the other embodiments described by example for temporary implant usemay be accomplished with the implantable systems of the presentembodiments.

[0430] Various particular modes of operation and intended therapies areadditionally provided as follows for further illustration.

[0431] According to one exemplary mode, ultrasound is delivered with apower between about 0.1 to about 1 W/cm2, operated at about 1.5 MHz, andat 1 kHz repetition with 100-200 micro-second burst (100-200 cycleburst) for example a total of between about 10 to 30 minutes daily. Thisis considered beneficial for example for stimulating bone growth.

[0432] According to another mode for more elevated heating, ultrasoundis delivered with a transducer emission power between about 0.5 to about2 W/cm2, at frequencies between about 5 to about 12 MHz, according tocontinuous wave delivery modes. Such may be continual all the time,though power limitations may require significant interface with externalpower sources, and tissue tolerance and/or degradation may result. Or,such may be limited in total time over a given period, such as forexample between about 5 to about 60 minutes/day. This is useful forexample to achieve moderate heating considered to be beneficial forexample to provide enhanced drug delivery therapy.

[0433] Where long-term, continual drug delivery enhancement is desired,a protocol of timed bursts may also be used as follows. Power may bebetween about 1 to about 30W/cm2, with bursts lasting between 50 to 200microseconds, repetition between about 1 Hz to about 5 kHz, and withultrasound frequencies between about 0.5 to about 15 MHz.

[0434] In still another mode, delivery of up to about 12 to about 15 MHzis considered beneficial for providing both heating in addition toacoustic stimulation.

[0435] Various time periods may be employed for ultrasound delivery,including for example periods of energy delivery of 5, 15, 30, 60, 120,or more minutes, which can be given multiple times per day, for extendedtime periods. These periods may represent continuous wave, pulsed burstwave, and may be in one treatment segment, or aggregated over variousspaced treatment intervals.

[0436] The parameters provided above for various different heatingmodalities are illustrative only, and may be varied according to aparticular combination of conditions and other related parameters foroperation, as elsewhere herein described. For example, where poweroutput is described by way of W/cm2, other parameters may be observedand/or controlled for desired results, such as for example power perlength of transducer treatment segment, e.g. 0.1-10 W per 1 cmapplicator length. In another example, where particular frequency rangesare desired, this may allow particular transducer constructions to beused for optimal overall results, such as adjusting the size to meet thefrequency of operation. For example, lower frequency transmissions aregenerally accomplished by transducers of larger wall thickness thanhigher frequency transmissions.

[0437] Therefore, various ultrasound transducers are considered usefulfor the present long-term implant embodiments and may be similar toothers previously described above, though in many cases will be modifiedto suit the different long-term implant needs, either by physicalconstraints, or according to different desired modes of operation.Examples of transducers considered suitable for many indicationsinclude, for example, providing the transducers according toconstructions that are adapted to operate between about 0.5 and about1.5 MHz., which would be useful for pulsing at low frequencies. Furtherdetails of a suitable transducer may include for example a PZT4 material(or 5 or 8) with wall thickness for example of about 0.058″ for 1.5 MHzvariety and about 0.174″ for 0.5 MHz varieties. Examples of appropriatelead wire assemblies include lead wires of about 0.002″ thickness foruse with low energy ultrasound applications.

[0438] Various materials for construction may be used to make the longterm implantable parts of the overall implant system, such as leadassemblies, e.g. coupling assembly 430 in FIGS. 66-68, or with respectto housing the transducer(s). Examples of suitable materials may includesilicone (NuSil™, e.g. NuSil™ 6640), Pebax™, and polyester (e.g.commercially available from Advanced Polymers) to the extent compatiblewith long term implantation. Moreover, coatings may be used on suchmaterials to enhance biocompatibility, including bioactive agents suchas anti-inflammatory, healing promoters, or other species of agents maybe used to meet the particular needs. Moreover, such agent coatings maybe adapted to elute from the implantable device surface to providetreatment to the tissue interfaced with or around the device, eitherwithin the zone of ultrasound treatment, or outside the targeted range(e.g. for protective therapy in view of the thermal conduction in thearea, such as to enhance protection of nerves).

[0439] Suture tags or other mechanisms such as fixation loops may beplaced along edges of applicators or transducer assembly for permanentattachment or semi-permanent fixation of device. Many such fixationdevices have been previously disclosed, and may be modified for useaccording to the present invention by one of ordinary skill based uponreview of this disclosure. In any event, the configuration and type ofsuch fixation device may be particularly tailored for the intendedenvironment where the transducer assembly is to be positioned forlong-term implantation. Such may affix to bone, connective tissue, ormuscle in the adjacent tissue. Moreover, fixation may also beimplemented for the control module and/or power source if also implantedwithin the body, as well as the respective coupling assembly orassemblies between the ultrasound treatment assembly and the respectivecontrol unit.

[0440] Pulsed ultrasound delivery is one particular mode for operatingthe implantable ultrasound delivery device of the present invention. Inone particular regard, such mode of operation is considered highlybeneficial for regeneration of various tissues. For example, therapeuticangiogenesis is the controlled induction or stimulation of new bloodvessel formation to reduce unfavorable tissue effects caused by localhypoxia and to enhance tissue repair. The effects of ultrasound on woundhealing, chronic ulcers, fracture healing and osteoradionecrosis may beexplained by the enhancement of angiogenesis. Optimum intensities ofbetween about 0.1 and about 0.4 W/cm2 (e.g. special average temporalaverage or “SATA”) with 1 MHz ultrasound stimulates the production ofangiogenic factors such as IL-8, fibroblast growth factor (bFGF) andvascular endothelial growth factor (VEGF) in cells such as osteoblastsand fibroblasts. Such is in particular applicable to long-term implantssuch as according to the present invention, though it is contemplatedthat repeat treatments with temporary implants may accomplish suchresults, such as according to the prior embodiments above. However, suchrepeated temporary modes of therapy would also require increasedmorbidity associated with repeat invasions into the body.

[0441] The following are further illustrative examples of modes ofoperation intended to provide certain desired results.

[0442] In one regard, a pulsed ultrasound delivery modality (e.g. lessthan or equal to about 70 microseconds) at about 5 MHz frequency ofoscillation is considered applicable for uses where nerve stimulation isdesired.

[0443] Low-intensity US accelerates regeneration of peripheral nerves,repairing of pseudarthrosis and bone fractures, will enhance formationof new bone tissue, osteogenesis and in the repairing of fractures.

[0444] Ultrasonic treatments at 0.5 W/cm2, 1.5 MHz, for durations of 5,15, and 25 min/day for four weeks, will accelerate bone formation at thefracture site for such durations. Ultrasound at 0.5 W/cm² arestimulatory to fracture repair, if given for example for about 15min/day.

[0445] Ultrasound at an intensity equal to about 0.4 W/cm², and atfrequency of about 1 MHz, will stimulate collagen synthesis in tendonfibroblasts in response to an injury of the connective tissue matrix,and also stimulate cell division during periods of rapid cellproliferation. Increasing the treatment time, such as for exampledoubling the treatment time to 40 minutes daily, will significantlyincrease the histologic quality of repair cartilage. Daily low-intensitypulsed ultrasound will have a positive effect on the healing ofosteochondral defects, with 40 minutes daily significantly increasingthe histologic quality of the repair cartilage.

[0446] Further more detailed information related to various modes ofthermal therapy and/or ultrasound delviery and related effects ontissue, and which provide further understanding of the variousoperational modes just described above according to using long-termimplantable devices according to the present invention, is generallydisclosed among the following references: Cook, J. L., J. L. Tomlinson,et al. (1999). “Induction of meniscal regeneration in dogs using a novelbiomaterial.” Am J Sports Med 27(5): 658-65; Cook, S. D., S. L. Salkeld,et al. (2001). “Improved cartilage repair after treatment withlow-intensity pulsed ultrasound.” Clin Orthop(391 Suppl): S231-43;Ramirez, A., J. A. Schwane, et al. (1997). “The effect of ultrasound oncollagen synthesis and fibroblast proliferation in vitro.” Med SciSports Exerc 29(3): 326-32; Reher, P., N. Doan, et al. (1999). “Effectof ultrasound on the production of IL-8, basic FGF and VEGF.” Cytokine11(6): 416-23; Rubin, C., M. Bolander, et al. (2001). “The use oflow-intensity ultrasound to accelerate the healing of fractures.” J BoneJoint Surg Am 83-A(2): 259-70; and Tsai, C. L., W. H. Chang, et al.(1992). “Preliminary studies of duration and intensity of ultrasonictreatments on fracture repair.” Chin J Physiol 35(1): 21-6; Foster K R,Widerhold M L, “Auditory responses in cats produced by pulsedultrasound,” J Acoust Soc Am. April 1978,63(4):1199-205. The disclosuresof these references are herein incorporated in their entirety byreference thereto.

[0447] Additional information related to various aspects generally ofimplantation in and around the spine, various additional modes ofoperating implantable energy delivery devices, or various differenttypes of conditions that may be also treated according to the presentinvention may be found in one or more of the following issued U.S. Pat.Nos. 6,233,488 to Hess; 6,493,592 to Leonard et al. Still furtherinformation is provided in one or more of the following U.S. patentapplication Publications: 2001/0049527 to Cragg; and 2002/0115945 toHerman et al. More information is also provided in the following PCTInternational Publication: WO 02/09808. Whereas the various disclosuresof these references do not describe a long-term, implantable therapeuticultrasound system such as according to the present invention, theirdisclosures may be considered helpful in gaining a completeunderstanding of certain aspects of the invention and various intendedenvironments of use, and therefore are herein incorporated in theirentirety by reference thereto.

[0448] Other modes of using the long-term implantable ultrasound therapydevices of the invention are also contemplated, including in combinationwith other therapies for cooperative effects. For example, theultrasound therapy may be used for or during local anesthesia. Examplesof disclosures intended to provide prolonged local anesthesia, such aswith respect to joints and other body spaces, are variously provided inthe following issued U.S. Pat. Nos. 6,046,187 to Berde et al.; 6,248,345to Goldenheim et al.; and 6,426,339 to Berde et al. The disclosures ofthese references are herein incorporated in their entirety by referencethereto.

[0449] Again, many different modes of operation, and intendedtherapeutic effects, have been provided to give a thorough understandingof applications by which the long-term implantable ultrasound therapysystems of the invention provide clinical benefit. However, other modes,specific designs and constructions, may be specially adapted forparticular applications and according to particular constraints, such asfor example patient anatomy, time of treatment, extent and area oftissue to treat, frequency of pain, etc. Such modifications areconsidered within the intended scope of the present invention, whichshould be considered broadly.

[0450] Moreover, ultrasound has been featured as the highly beneficialtherapeutic energy source of choice for the various embodiments hereinshown and described. However, other energy sources should be consideredwithin the intended scope of various aspects of the invention to theextent capable of achieving such desired, novel results. Examples ofsuch aspects include: active cooling (including at the transducer,interfacing tissue, or non-targeted tissue); directional energycoupling; focused energy delivery (e.g. converging energy signals); useof coupling members to achieve uniform energy delivery into tissueinterface; thermal treatments according to specified thermal dosing ortemperature ranges to achieve certain desired tissue responses; andcoupling of energy into tissues with desired temperature elevations atvarious depths of tissues (and within desired ranges of time).

[0451] Although the description above contains many specificities, theseshould not be construed as limiting the scope of the invention but asmerely providing illustrations of some of the presently preferredembodiments of this invention. Thus the scope of this invention shouldbe determined by the appended claims and their legal equivalents.Therefore, it will be appreciated that the scope of the presentinvention fully encompasses other embodiments which may become obviousto those skilled in the art, and that the scope of the present inventionis accordingly to be limited by nothing other than the appended claims,in which reference to an element in the singular is not intended to mean“one and only one” unless explicitly so stated, but rather “one ormore.” All structural, chemical, and functional equivalents to theelements of the above-described preferred embodiment that are known tothose of ordinary skill in the art are expressly incorporated herein byreference and are intended to be encompassed by the present claims.Moreover, it is not necessary for a device or method to address each andevery problem sought to be solved by the present invention, for it to beencompassed by the present claims. Furthermore, no element, component,or method step in the present disclosure is intended to be dedicated tothe public regardless of whether the element, component, or method stepis explicitly recited in the claims. No claim element herein is to beconstrued under the provisions of 35 U.S.C. 112, sixth paragraph, unlessthe element is expressly recited using the phrase “means for.”

What is claimed is:
 1. An ultrasound energy delivery system forproviding long term treatment to a region of tissue associated with askeletal joint, comprising: a long-term implantable ultrasound treatmentassembly with an ultrasound transducer; a skeletal joint deliveryassembly that is adapted to deliver the ultrasound treatment assemblyinto the body with the ultrasound transducer positioned at a locationwithin the body associated with the skeletal joint; and wherein theultrasound treatment assembly is adapted to provide long-term deliveryof a therapeutic level of ultrasound energy from the location and intothe region of tissue.
 2. The system of claim 1, wherein the skeletaljoint delivery assembly comprises a needle.
 3. The system of claim 1,wherein the skeletal joint delivery assembly comprises a cannula with asharpened tip that is adapted to puncture a tissue barrier associatedwith the joint.
 4. The system of claim 1, wherein: the skeletal jointdelivery assembly comprises a guidewire; and the ultrasound treatmentassembly is adapted to be delivered over the guidewire to the location.5. The system of claim 1, wherein: the skeletal joint delivery assemblycomprises a cannula; and the ultrasound treatment assembly is adapted tobe delivered through the cannula to the location.
 6. The system of claim1, wherein the ultrasound treatment assembly is adapted to be steerableto the location.
 7. The system of claim 6, wherein the ultrasoundtreatment assembly is located on a deflectable member.
 8. The system ofclaim 1, wherein the ultrasound treatment assembly is located on apre-shaped support member.
 9. The system of claim 1, wherein theultrasound transducer is constructed to provide directional thermaltherapy to the region of tissue.
 10. The system of claim 9, wherein theultrasound transducer is constructed to deliver a converging field ofenergy to the region of tissue.
 11. The system of claim 9, wherein theultrasound transducer is constructed to deliver a diverging field ofultrasound energy to the region of tissue.
 12. The system of claim 9,wherein the ultrasound transducer is constructed to deliver asubstantially collimated field of ultrasound energy to the region oftissue.
 13. The system of claim 1, wherein the ultrasound treatmentassembly comprises a coupling member positioned so as to coupleultrasound energy from the ultrasound transducer to the region oftissue.
 14. The system of claim 13, wherein: the coupling membercomprises a radially extendable member that is adapted to radiallyextend from a first contracted position relative to the ultrasoundtransducer to a second extended position relative to the ultrasoundtransducer that is further away from the ultrasound transducer than thefirst position; and the ultrasound transducer is adapted to delivery theultrasound energy to the region of tissue via the coupling member withthe radially extendable member in the second extended position.
 15. Thesystem of claim 14, wherein: the extendable member comprises aninflatable balloon that is adapted to be coupled toga source ofinflation medium and to inflate with a pressurized volume of fluid fromthe source; and the ultrasound transducer is adapted to deliver theultrasound energy to the tissue via the fluid and inflatable balloon.16. The system of claim 1, further comprising: a temperature controlsystem that is adapted to control the temperature of at least one of theultrasound transducer or a tissue interface between a region of tissueand the ultrasound treatment assembly during ultrasound energy deliveryto the region of tissue.
 17. The system of claim 16, wherein theultrasound treatment assembly is adapted to actively cool the ultrasoundtransducer or tissue interface.
 18. The system of claim 1, furthercomprising: a cooling system with a controller; wherein the ultrasoundtreatment device is adapted to couple to the cooling system; and whereinthe cooling system via the controller is adapted to cool at least one ofthe ultrasound transducer and a region of tissue being affected by theultrasound delivery.
 19. The system of claim 18, wherein the coolingsystem is adapted to cool the ultrasound transducer with a fluid havinga temperature less than room temperature.
 20. The system of claim 18,wherein the fluid temperature is about zero degrees C.
 21. The system ofclaim 18, wherein the fluid temperature is equal to or greater thanabout room temperature.
 22. The system of claim 18, wherein the coolingsystem comprises: a source of fluid medium; and wherein the coolingsystem is adapted to circulate fluid from the source through theultrasound treatment device so as to cool the ultrasound transducer. 23.The system of claim 1, further comprising: an ultrasound control systemwith a temperature monitoring system, a controller, and an ultrasounddrive system; wherein the ultrasound treatment assembly is adapted tocouple to the ultrasound control system; and wherein the ultrasoundcontrol system is adapted to control the ultrasound energy being emittedby the ultrasound transducer as a function of at least one monitoredtransient parameter.
 24. The system of claim 23, wherein the at leastone parameter comprises a parameter related to the operation of theultrasound transducer.
 25. The system of claim 24, wherein the at leastone parameter comprises impedance, voltage, current, power, temperature,reflected power, or rates of change thereof.
 26. The system of claim 23,wherein the at least one parameter comprises a parameter related to theeffects of ultrasound delivery from the ultrasound transducer in tissue.27. The system of claim 26, wherein the ultrasound control system isadapted to control operation of the ultrasound delivery assembly basedupon a temperature monitored at a coupling tissue surface between thetissue and the ultrasound delivery assembly.
 28. The system of claim 26,wherein the at least one parameter comprises thermal dose, tissuetemperature, depth of thermal penetration, pulse duration, frequencybetween pulses, or rates of change thereof.
 29. The system of claim 23,wherein the at least parameter is empirically based.
 30. The system ofclaim 23, wherein the at least one parameter comprises a value that ismonitored during ultrasound therapy.
 31. The system of claim 23, whereinthe at least one parameter comprises a value that is calculated basedupon another measured parameter.
 32. The system of claim 23, wherein thecontroller is adapted to control the operation of the ultrasoundtransducer such that the temperature in at least a portion of the tissuewithin at least a 4 mm depth from the ultrasound transducer is elevatedto at least about 70 degrees C. in response to ultrasound energy beingdelivered thereto from the ultrasound transducer.
 33. The system ofclaim 32, wherein the controller is adapted to control the operation ofthe ultrasound transducer such that the temperature of the tissue withinthe 4 mm depth is elevated to at least about 75 degrees C. in responseto the ultrasound energy delivery.
 34. The system of claim 23, whereinthe controller is adapted to control the operation of the ultrasoundtransducer such that the temperature in tissue within up to at leastabout a 7 mm depth from the ultrasound transducer is elevated to atleast about 70 degrees C.
 35. The system of claim 23, wherein thecontroller is adapted to control the operation of the ultrasoundtransducer such that the temperature in tissue within up to at least a10 mm depth from the ultrasound transducer is elevated to greater thanabout 45 degrees C.
 36. The system of claim 23, wherein the controlleris adapted to control the operation of the ultrasound transducer suchthat the temperature within the tissue at up to at least a 4 mm depthfrom the ultrasound transducer is elevated to an elevated temperature ofno more than about 75 degrees C. or less.
 37. The system of claim 36,wherein the controller is adapted to control the operation of theultrasound transducer such that the temperature of the tissue within the4 mm depth is elevated to an elevated temperature of no more than about70 degrees C. or less.
 38. The system of claim 23, wherein thecontroller is adapted to control the operation of the ultrasoundtransducer such that the temperature in tissue within up to at least a 7mm depth from the ultrasound transducer is elevated to at least 70degrees C.
 39. The system of claim 23, wherein the controller is adaptedto control the operation of the ultrasound transducer such that thetemperature in tissue within up to at least a 10 mm depth from theultrasound transducer is elevated to greater than 45 degrees C.
 40. Thesystem of claim 23, wherein the at least one monitored parameter relatesto at least one of bone growth, pain, or a physiologic function affectedby nervous stimulation at the location.
 41. The system of claim 23,wherein the controller comprises a long-term implant that is adapted tobe implanted within the body of the patient.
 42. The system of claim 41,wherein the controller comprises a power source.
 43. The system of claim42, wherein the power source is rechargeable.
 44. The system of claim43, wherein the power source is adapted to be recharged by exposure to amagnetic field across a skin barrier of the patient.
 45. The system ofclaim 41, wherein the controller comprises a microprocessor.
 46. Thesystem of claim 45, wherein the controller comprises a monitoringassembly.
 47. The system of claim 45, wherein the controller comprises adata storage system.
 48. The system of claim 45, wherein the controlleris adapted to communicate across the patient's skin barrier via wirelesscommunications system so as to provide telemetry with respect to theultrasound therapy.
 49. The system of claim 48, further comprising anexternal assembly that is adapted to communicate with the controller viawireless signals so as to receive telemetry with respect to theultrasound therapy.
 49. The system of claim 23, further comprising: acoupling assembly that is adapted to couple to the ultrasound treatmentassembly and at least one externally located coupler across thepatient's skin barrier; and wherein the controller is adapted to belocated externally of the patient's body and to couple to the externalcoupler so as to control the ultrasound treatment assembly for providingultrasound therapy.
 50. The system of claim 1, wherein the ultrasoundtreatment assembly is adapted to heat tissue up to a distance of atleast about 4 mm from the ultrasound transducer to a temperature of atleast about 70 degrees C.
 51. The system of claim 50, wherein theultrasound heating assembly is adapted to heat the tissue within the 4mm depth to a temperature of at least about 75 degrees C.
 52. The systemof claim 51, wherein the ultrasound treatment assembly is adapted toheat the tissue at least about 4 mm away from the transducer to thetemperature of at least about 75 degrees C. in less than about 5 minutesof ultrasound energy delivery into the tissue.
 53. The system of claim1, wherein the ultrasound treatment assembly is adapted to heat tissueup to a distance of at least about 7 mm from the ultrasound transducerto a temperature of at least about 70 degrees C.
 54. The system of claim1, wherein the ultrasound treatment assembly is adapted to heat tissueup to a distance of at least about 10 mm from the ultrasound transducerto a temperature of at least about 45 degrees C.
 55. The system of claim1, wherein the ultrasound treatment assembly is adapted to heat tissueup to a distance of at least 4 mm from the ultrasound transducer to atemperature of no more than about 75 degrees C. or less.
 56. The systemof claim 1, wherein the ultrasound treatment assembly is adapted to bepositioned within an intervertebral disc and to heat at least portion ofthe disc.
 57. The system of claim 1, wherein the ultrasound treatmentassembly is adapted to be positioned at a location adjacent to anintervertebral disc and to provide thermal therapy to the intervertebraldisc from that location.
 58. The system of claim 1, wherein theultrasound treatment assembly is adapted to be positioned within atleast a portion of a vertebral body or posterior vertebral element andto provide thermal therapy at least in part to the vertebral body. 59.The system of claim 1, wherein the ultrasound treatment assembly isadapted to be positioned at a location adjacent to a vertebral body orposterior vertebral element and to delivery ultrasound energy to atleast a portion of the vertebral body.
 60. The system of claim 1,wherein the ultrasound treatment assembly and the skeletal jointdelivery assembly are integrated.
 61. The system of claim 60, wherein:the skeletal joint delivery assembly comprises a substantially rigidprobe device with a proximal end portion and a distal end portion; andthe ultrasound treatment assembly is located along the distal endportion.
 62. The system of claim 1, wherein the ultrasound treatmentassembly and skeletal joint delivery assembly are separate devices thatcooperate together.
 63. The system of claim 1, wherein the skeletaljoint delivery assembly comprises a spinal joint delivery assembly. 64.The system of claim 1, wherein the ultrasound treatment assembly andspinal joint delivery assembly together comprise an external directionalultrasound thermal therapy system.
 65. The system of claim 1, whereinthe ultrasound treatment assembly and spinal joint delivery assemblytogether comprise an internal directional ultrasound thermal therapysystem.
 66. The system of claim 1, wherein the ultrasound treatmentassembly comprises a single curvilinear ultrasound transducer.
 67. Thesystem of claim 1, wherein the ultrasound treatment assembly comprisesmultiple curvilinear ultrasound transducers.
 68. The system of claim 1,wherein the ultrasound transducer is adapted to emit directed,therapeutic ultrasound energy within a treatment zone of less than orequal to about one hundred eighty degrees relative to the ultrasoundtransducer.
 69. The system of claim 68, wherein the treatment zone isless than or equal to about ninety degrees.
 70. The system of claim 1,wherein the ultrasound transducer is comprises a curved shape with aradius of curvature that is around a reference axis that is transverseto the longitudinal axis of a support member upon which the ultrasoundtransducer is mounted.
 71. The system of claim 1, wherein the ultrasoundtransducer is comprises a curved shape with a radius of curvature thatis around a reference axis that is aligned with the longitudinal axis ofa support member upon which the ultrasound transducer is mounted. 72.The system of claim 1, further comprising: a long-term implantableultrasound controller that is adapted to control ultrasound energydelivery from the ultrasound treatment assembly.
 73. The system of claim72, wherein the controller is adapted to operate the ultrasoundtreatment assembly according to a set of operating parameters adapted tostimulate bone growth.
 74. The system of claim 73, wherein the set ofoperating parameters comprises: a transmission power level between about0.1 to about 1 W/cm2, and about 1.5 MHz, and at about 1 kHz repetition,and with burst intervals between about 100 to about 200 micro-seconds.75. The system of claim 74, wherein the set of parameters furthercomprises: total aggregate time of ultrasound delivery is between about10 to 30 minutes per day for at least one day of long-term ultrasoundtreatment.
 76. The system of claim 72, wherein the controller is adaptedto operate the ultrasound treatment assembly according to a set ofoperating parameters adapted to enhance drug delivery therapy to thetissue at the location.
 77. The system of claim 75, wherein the set ofoperating parameters comprises: transmission power between about 0.5 toabout 2 W/cm2, operating frequency between about 5 to about 12 MHz, andcontinuous wave delivery.
 78. The system of claim 77, wherein the set ofparameters further comprises: aggregate time of ultrasound deliverybetween about 5 to about 60 minutes per day over at least one day oflong-term ultrasound treatment.
 79. The system of claim 71, wherein thecontroller is adapted to operate the ultrasound transducer according tothe following set of operating parameters: transmission power betweenabout 1 to about 30 W/cm2, transmission bursts lasting between 50 to 200microseconds, repetition between bursts between about 1 Hz to about 5kHz, and at ultrasound operating frequencies between about 0.5 to about15 MHz.
 80. The system of claim 71, wherein the controller is adapted tooperate the ultrasound transducer at operating frequencies between about12 to about 15 MHz.
 81. The system of claim 71, wherein the controlleris adapted to operate the ultrasound transducer so as to provide thermaltherapy in addition to acoustic nervous stimulation.
 82. The system ofclaim 71, wherein the controller is adapted to operate the ultrasoundtreatment assembly according to a set of operating parameters adapted tostimulate nervous impulses at the location.
 83. The system of claim 75,wherein the set of operating parameters comprises: pulsed ultrasounddelivery over periods of less than or equal to about 70 microseconds,and operating frequency of about 5 MHz.
 84. The system of claim 71,wherein the controller is adapted to operate the ultrasound treatmentassembly according to a set of operating parameters adapted toaccomplish at least one of: regenerate peripheral nerves, repairpseudarthrosis and bone fractures, stimulate bone growth, and stimulateosteogenesis with respect to repairing fractures.
 85. The system ofclaim 84, wherein the set of operating parameters comprises:transmission power of about 0.5 W/cm2, operating frequency of about 1.5MHz, treatment interval durations of between about 5 to about 25 minutesper day for at least one day over a long-term treatment regimen.
 86. Thesystem of claim 85, wherein the set of operating parameters furthercomprises total period of therapy of about four weeks.
 87. The system ofclaim 84, wherein the set of operating parameters comprises: ultrasoundtransmission at about 0.5 W/cm² aggregate daily treatment of about 15minutes per day for at least one day over a long-term treatment regime.88. A skeletal joint therapy device, comprising: a long-term implantablethermal treatment assembly with an energy emitter; wherein the thermaltreatment assembly is adapted to be implanted at a location within abody of a patient; wherein the energy emitter is adapted to follow along-term protocol for energy delivery into a region of tissueassociated with a skeletal joint; and wherein the thermal treatmentassembly is adapted to heat tissue up to a distance of at least 4 mmfrom the energy emitter to a temperature of at least 75 degrees C., andis adapted to heat tissue up to a distance of at least about 7 mm fromthe energy emitter to a temperature of at least about 55 degrees C., andis adapted to heat tissue up to a distance of at least about 10 mm fromthe energy emitter to a temperature of at least about 45 degrees C. 89.The device of claim 88, wherein the thermal treatment assembly comprisesan ultrasound transducer.
 90. The device of claim 88, wherein the devicefurther comprises a long-term implantable controller that is adapted tobe coupled to and control operation of the thermal treatment assemblyaccording to the long-term protocol and according to a set of operatingparameters.
 91. The device of claim 90, wherein the controller comprisesa long-term internal implant.
 92. The device of claim 90, wherein thecontroller comprises a long-term external implant that is adapted to becoupled to the thermal treatment assembly across a skin barrier.
 93. Thedevice of claim 90, wherein the controller comprises a power source witha rechargeable battery.
 94. The device of claim 90, wherein thecontroller is adapted to provide telemetry with respect to the thermaltherapy to an external assembly.
 95. A long-term implantable ultrasoundthermal treatment system, comprising: a long-term implantable ultrasoundtreatment assembly with an ultrasound transducer; a long-termimplantable coupling probe having a elongate body with a proximal endportion and a distal end portion; the distal end portion has a proximalsection with a longitudinal axis, a distal section with a distal tip,and a bend between the proximal and distal sections; wherein theultrasound treatment assembly is located along the distal section of thedistal end portion and extending at an angle from the proximal section;wherein the distal end portion is adapted to be implanted within thebody of a mammal by manipulating the proximal end portion such that theultrasound treatment assembly is positioned at a location associatedwith a region of tissue to be treated; wherein the proximal end portionis also adapted to be implanted within the body with the distal endportion implanted with the ultrasound treatment assembly at thelocation; and wherein the ultrasound treatment assembly is adapted tofollow a long-term therapeutic protocol of ultrasound energy deliveryinto the region of tissue from the location within the body.
 96. Thesystem of claim 95, wherein the system is substantially MRI compatible.97. The system of claim 95, wherein the ultrasound transducer isconstructed to provide directional ultrasound delivery to the region oftissue.
 98. The system of claim 95, wherein the ultrasound transducer isconstructed to deliver a converging field of ultrasound energy to theregion of tissue.
 99. The system of claim 95, wherein the ultrasoundtransducer is constructed to deliver a diverging field of ultrasoundenergy to the region of tissue.
 100. The system of claim 95, wherein theultrasound transducer is constructed to deliver a substantiallycollimated field of ultrasound energy to the region of tissue.
 101. Thesystem of claim 95, wherein the ultrasound treatment assembly comprisesa coupling member positioned so as to couple ultrasound energy from theultrasound transducer to the region of tissue.
 102. The system of claim95, further comprising a temperature control system coupled to theultrasound treatment assembly.
 103. The system of claim 95, furthercomprising a drug delivery system that is adapted to deliver a drug intothe region of tissue when the ultrasound treatment assembly isdelivering the therapeutic ultrasound to the region of tissue.
 104. Along-term implantable ultrasound thermal therapy system, comprising: along-term implantable ultrasound heating assembly with an ultrasoundtransducer and that is adapted to be implanted within a body of a mammalwith the ultrasound transducer positioned at a location such that theultrasound transducer is adapted to deliver a ultrasound energy into atargeted region of tissue in the body from the location; a long-termultrasound therapy control system that is adapted to be coupled to theultrasound heating assembly; and wherein the long-term implantableultrasound therapy control system is adapted to be coupled to andcontrol operation of the ultrasound heating assembly while it isimplanted at the location according to a long-term ultrasound thermaltherapy protocol.
 105. The system of claim 104, wherein the therapycontrol system is adapted to operate the ultrasound transducer such thata substantial portion of the region of tissue being heated by theultrasound heating assembly does not exceed a maximum temperature of atleast about 70 degrees C.
 106. The system of claim 104, wherein thetherapy control system is adapted to control operation of the ultrasoundheating assembly such that a substantial portion of the region of tissuebeing heated by the ultrasound heating assembly does not exceed amaximum temperature of at least about 75 degrees C.
 107. The system ofclaim 104, wherein the control system comprises a long-term internallyimplantable controller that is adapted to be coupled with and controlthe ultrasound heating assembly from within the body.
 108. The system ofclaim 104, wherein the control system comprises a long-term externallyimplantable controller that is adapted to be coupled with and controlthe ultrasound heating assembly from externally of the body and across askin barrier.
 109. A long-term directional ultrasound spinal thermaltherapy system, comprising: a long-term implantable ultrasound deliveryassembly with a directional ultrasound transducer that is adapted to bepositioned at a location associated with a spinal joint and to deliver adirected, therapeutic amount of ultrasound energy from the location andto a region of tissue associated with the spinal joint.
 110. A long-termimplantable skeletal joint ultrasound delivery system, comprising: along-term implantable ultrasound treatment assembly with an ultrasoundtransducer and a coupling member; wherein the ultrasound deliveryassembly is adapted to be implanted within a body of a mammal with theultrasound transducer positioned at a location within the bodyassociated with a skeletal joint; and wherein the ultrasound transduceris adapted to deliver a therapeutic amount of ultrasound energy to aregion of tissue associated with the skeletal joint via the couplingmember and according to a long-term ultrasound treatment protocol. 111.A long-term implantable ultrasound thermal therapy system, comprising: along-term implantable ultrasound heating assembly that is adapted to beimplanted at a location within a body of a mammal so as to deliverultrasound energy into a region of tissue in the body from the location;and a control system that is adapted to be coupled to the ultrasoundheating assembly and to control operation of the ultrasound heatingassembly according to a long-term ultrasound thermal therapy protocoland such that a region of tissue being heated by the ultrasound heatingassembly exceeds a temperature of at least about 70 degrees C.
 112. Anultrasound thermal therapy system, comprising: a long-term implantableultrasound heating assembly that is adapted to be implanted within abody of a patient and to couple with an ultrasound controller from thelocation, and also with a curvilinear ultrasound transducer having aconcave surface with a radius of curvature around a reference axis suchthat ultrasound energy transmitted therefrom converges into a region oftissue at a target location.
 113. The system of claim 1 12, wherein thereference axis is transverse to the longitudinal axis of the distal endportion.
 114. A method for providing long-term, invasive treatment for amedical condition associated with a skeletal joint within a body of apatient, comprising: delivering a therapeutic level of ultrasound energyto a region of tissue associated with the joint from a location withinthe body of the patient and according to a long-term ultrasound therapyprotocol.
 115. A method for providing long-term, invasive treatment fora medical condition associated with a skeletal joint within a body of apatient, comprising: delivering sufficient energy to a region of tissueassociated with the skeletal joint that is sufficient to necrosenociceptive nerve fibers or inflammatory cells in such tissue regionwithout substantially affecting collagenous structures associated withthe skeletal joint and according to us of a long-term energy deliveryimplant and according to a long-term energy delivery therapeuticprotocol.
 116. A method for providing long-term, invasive treatment to aregion of tissue associated with an intervertebral disc in a body of apatient, comprising: implanting a long-term ultrasound transducerimplant at a location within the body such that a therapeutic level ofultrasound may be coupled from the transducer to the tissue andaccording to a long-term ultrasound therapy protocol.
 117. A method forproviding long-term treatment to a patient, comprising: deliveringenergy to a region of tissue associated with the spine over a period oftime associated with long-term therapy, wherein such tissue does notexperience a rise in temperature of more than about 55 degrees C.
 118. Amethod for providing long-term treatment to a patient, comprising:delivering energy to a region of tissue associated with the spine,wherein such energy delivery is between about 10 and about 300equivalent minutes at 43 degrees C., and according to a long termthermal therapy protocol.
 119. A method for providing long-term invasivetreatment for a medical condition associated with an intervertebral discwithin a body of a patient, comprising: delivering a therapeutic levelof ultrasound energy to a region of tissue associated with anintervertebral disc from a location within the body of the patient andaccording to a long-term ultrasound therapy protocol.
 120. A method forproviding long-term medical treatment for a medical condition associatedwith a joint between two bony structures in a body of a patient,comprising: implanting an ultrasound transducer at a location within thepatient's body associated with the joint for a long-term; emittingultrasound energy from the transducer at the location so as to provide atherapeutic effect to at least a portion of the joint and according to along-term ultrasound therapy protocol.
 121. A method for providinglong-term treatment to a patient, comprising: introducing an ultrasoundtransducer into a body of a patient; implanting the ultrasoundtransducer at a location within the patient that is adjacent to at leastone of an annulus fibrosus of an intervertebral disc, a nucleus pulposusof the intervertebral disc, or a vertebral body associated with a spinaljoint in the body; and emitting ultrasound energy from the ultrasoundtransducer at the location and according to a long-term ultrasoundtherapy protocol.
 122. A method for providing long-term ultrasoundenergy delivery within a body of an animal, comprising: introducing anultrasound transducer into a body of a patient; implanting theultrasound transducer at a location within the patient that is within atleast one of an annulus fibrosus of an intervertebral disc, a nucleuspulposus of the intervertebral disc, or a vertebral body associated witha spinal joint in the body; and emitting ultrasound energy from theultrasound transducer at the location and according to a long-termthermal therapy protocol.
 123. A method for providing long-term thermaltherapy to a patient, comprising: ultrasonically heating a region oftissue associated a spinal joint to a temperature between about 45 toabout 90 degrees C. over a period of time associated with a long-termimplant and so as to cause a therapeutic result in the tissue.